Tailored therapy in long QT syndrome
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1 Tailored therapy in long QT syndrome Dominic Abrams St. Bartholomew s & Great Ormond Street Hospitals London, UK Disclosures None
2 Tailored therapy in long QTS Which patients should have tailored therapy...?... all of them. High variability Life threatening episodes in 1st year of life Asymptomatic life long Genetic, environmental & individual factors
3 Tailored therapy in long QTS Beta-blockers have become the mainstay of treatment for long QT syndrome Marked reduction in mortality Schwartz 1975 Projected clinical course Early identification of high risk cases Management of treatment failures
4 Tailored therapy
5 Long QT syndrome QT prolonging drugs 5
6 Long QT syndrome QT prolonging drugs
7 Long QT syndrome QT prolonging drugs
8 Long QT syndrome QT prolonging drugs
9 Long QT syndrome QT prolonging drugs -
10 Age Long QT in infancy
11 Age Long QT in infancy 23 neonates - QTc 558 ± 62ms Syncope (2), torsades des pointes (7), cardiac failure (6) Neonatal bradycardia Sinus bradycardia (8) - KCNQ1 2:1 AV block (15) - KCNH2/compound Beta-blockers alone (10), beta-blockers with PPM (13) 3 deaths
12 Age Long QT in infancy Early presentation with severe phenotype SCN5A >> KCHN2 >>>> KCNQ1 Combined therapy Beta-blockers ± mexilitine Pacemaker Left cardiac sympathetic denervation Implantable cardioverter-defibrillators Schwartz Circulation 2004
13 Long QT syndrome & sex Goldenberg JACC 2008
14 Long QT syndrome & sex Estrogen effects on IKr Seth JACC 2007 Buber Circulation 2011
15 QTc interval
16 Normal QTc interval
17 Normal QTc interval
18 Severe QTc prolongation Long QT 3 (1231 G>A; V411M)
19 Long QT genotype
20 Genotype Long QT syndrome & beta-blockers Cardiac events on beta-blockers LQT1-10% LQT2-23% LQT3-32%
21 Genotype Long QT1 & beta-blockers 26 of 216 patients (12%) presented with cardiac arrest 9/26 taking QT prolongingdrugs None implanted with ICD All compliant with betablockers & avoided QT prolonging drugs No further cardiac arrest or SCD 21
22 Genotype Long QT3 & beta-blockers Schwartz Heart Rhythm 2009
23 Implantable cardioverterdefibrillators
24 Implantable cardioverter-defibrillators
25 Implantable cardioverter-defibrillators Individualised ICD settings Long detection times 45/60 + Single VF zone - >214bpm No ATP Atrial lead AF/SVT discrimination Continue beta-blockade
26 Severe QTc prolongation Compound KCNQ1/KCNH2 Symptomatic despite ICD & BB Sympathectomy 12-lead Holter EPS & ablation
27 Long QT syndrome Atrial pacing Abrams BMJ 2010
28 Long QT syndrome Atrial pacing
29 Long QT syndrome Genetic modification
30 Long QT syndrome Genetic modification South African group of long QT 1 - QTc ms Single pathogenic mutation in KCNQ1 - A341V Assessed for common variants in NOS1AP 2 variants increased QTc and disease severity
31 hipsc for Modelling Cardiovascular Disease Genetic condition Patients Somatic Cells (informed consent: skin, teeth, gingival, blood) Reprogramme & passage Differentiation Analysis e.g. skin heart Long QT Syndrome Chris Denning, University of Nottingham
32 LQT2 Case Study Ala PAT QTc 455msec QTc 571msec G>A LQT2 Thr MAT Pore QTc 514msec NH3+ COO- Chris Denning, University of Nottingham
33 20mV 20mV Phenotype of LQT2-hiPSC CMs Ventricular 0mV 200 msec hesc 419ms HF-hiPSC 386ms LQT2-hiPSC 881ms MAT-hiPSC 704ms Control LQT2 KCNH2-1681G>A Spontaneou s Isoprenaline Isoprenaline + Propranolol 0mV 200 msec Matsa et al., 2011 Eur Heart J. Chris Denning, University of Nottingham
34 hipsc for Modelling Cardiovascular Disease Potential in drug screening and disease modelling Beat for at least 22 months X 4 X 1 ~30 hipsc lines with electrical, structural, survival disorders Drug & gene therapy X 2 Chris Denning, University of Nottingham X 3
35 Conclusions Treatment in long QT syndrome should be tailored to the patient Highly variable condition Manage the patient (phenotype) Phenotypic expression affected by multiple factors New technologies may allow better individual modeling and highly individualised treatment strategies
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