When VF is the endpoint, wait and see is not always the best option.

Transcription

1 Being free of symptoms does not necessarily mean free of arrhythmias. This Holter is from a asymptomatic 48 years old female with LQT2 When VF is the endpoint, wait and see is not always the best option. Viskin, Treating LQTS in the ICD era. Circulation

2 Asymptomatic channelopathy Asymptomatic channelopathies. Avoid drugs. Avoid sports? Avoid swimming? Report symptoms. Learn CPR (EAD) Fever! General measures: 1. Report symptoms. 2. Teach CPR and EAD. 3. Activities to avoid. 4. Drugs to avoid. 5. Drugs to take. Beware of genetics 2

3 There is a new diagnostic test in town: LQTS: One word about diagnosis Distribution of QTc Values Number of Persons Gene Carriers of Long QT Syndrome and Non-Carriers Carriers of Long QT Non-carriers QTc (seconds) G. Michael Vincent, M.D. Baseline RR 880, QT 480 ms QTc 512 ms Maximal tachycardia RR 680, QT 480 ms QTc 582 ms Return to baseline RR 880, QT 530 ms QTc 565 ms 3

4 Treat everybody Wait for first syncope and then treat Compliance with beta-blockers and of avoidance of QTprolonging drugs: Risk of cardiac arrest in LQT1 Risk of cardiac arrest Before Beta-blockers Avoidance of IKr blockers 0 8.5% YES 53% NO On Beta-blockers 0.6% YES 28% NO Always compliant Vincent, Circulation Balancing risk: Do Not Risk of cardiac arrest as first event vs. risk of therapy. 4

5 Life-long probability of QT-related symptoms First symptom Cardiac arrest. 60% 60% 40% 40% 20% 20% Age (in years) Age (in years) Goldenberg & Moss. LQTS, State of the Art. JACC 2008 Cumulative probability of Cardiac Arrest Probability of cardiac arrest during childhood depending on the symptoms experienced during infancy Cardiac arrest in the 1 st year Syncope in the 1 st year No cardiac event in 1 st year Age (years) Spazzolini, JACC What to do when beta-blocker therapy is not tolerated? Fatigue (BB-zombies). Asthma. Beta-blockers for all and all for beta-blockers. 5

6 When is beta-blocker therapy simply NOT ENOUGH? Sleep recording of LQT2 on beta-blockers Probability of cardiac event. Risk of cardiac events in long-qt patients patients with LQTS with and asthma asthma. Beta-blockers reduce that risk RISK. Beta-agonists increase the arrhythmic risk for 80% 60% 40% 20% On beta-agonist inhalers Not on beta-agonists Age (in years) Thottathil, Am J Cardiol 2008 Risk of cardiac arrest and QTc in LQTS. Risk of cardiac arrest 50% 40% 30% QTc >530 20% QTc: % QTc: Age (years) Kaufman, Heart Rhythm 2008 Risk of death in the LQTS when a sibling has died. Kaufman, Heart Rhythm

7 transmembrane C-terminus Prognosis by protein domain affected? Adjusted Hazard Ratio for Cardiac Events by Maximum QTc Dicotomized at different QTc intervals. Hazard Ratio for Cardiac Events. 95% confidence intervals. missense non-missense KCNQ1 (LQT1) HR= 2.74 HR= 2.76 HR= 1.83 HR= 2.04 dominant (-) haploinsufficiency Moss et al., 2007 QTc >480 QTc >490 QTc >500 QTc >510 Goldenberg, JACC 2006 STATE OF THE ART PAPER The Long QT Syndrome. JACC 2008 Goldenberg and Moss Risk factors for life-threatening events. Hazard Ratio. Reduction with BB Childhood Male gender % QTc > Adolescence QTc > % Adulthood Female gender % QTc > QTc LQT

8 When is beta-blocker therapy not enough for asymptomatic patients with LQTS? A personal view. One word about diagnosis. LQT1 with deafness (JLN) or less than 100% compliance. Left cardiac sympathetic dennervation. LQT2 with very long QT: Cardiac pacemaker or ICD. Same patient. Holter recording while running. 12 years old. Bisoprolol 5 mg Maximal sinus rate achieved = 130/min BD: 12-year old boy, asymptomatic CPVT carrier. Symptom limited exercise test on bisoprolol 5 mg Maximal heart rate 140 beats/min. BzgDr 8

9 CPVT is a malignant disease. 101 patients 61 symptomatic 40 asymptomatic No β-blockers Prophylactic β-blockers 20% had arrhythmias 2% had cardiac arrest 25% had arrhythmias 6% had cardiac arrest Follow-up years. Teach CPR to family members, school-teachers, etc. EAD for home-use EAD for school-use 300 beats/min Risk for cardiac arrest in CPVT At 4 years At 8 years 1% Β-blockers 18% NO ΒB 25% 11% Β-blockers NO ΒB Hayashi, Circulation

10 Prevention of exercise-induced arrhythmias in CPVT A Baseline C Atenolol Arrhythmic storm in a 22-years old female. 1 sec B No medications II V2 1 sec 1 sec D Atenolol + verapamil 1 sec 1 sec V5 avf V4 V6 Rosso, Viskin; Heart Rhythm Courtesy of M. Boulos, (Rambam, Haifa) 2005 Therapy of asymptomatic CPVT A personal view. ALL asymptomatic CPVT carriers (including those with negative exercise) test MUST receive beta-blockers. Beta-blockers should be administered at maximally tolerated doses. Beta-blockers + flecainide (or LCSD) is a good idea for all CPVT patients, especially those with exercise induced arrhythmias. VT /min Ventricular arrhythmias in Casq2 -/- mice. Effects of flecainide. Bidirectional VT in knock-in mouse Control Flecainide Exercise Hours after exercise Watanabe, Nature Medicine

11 Asymptomatic Brugada syndrome a cardiac ticking bomb? Sacher, Circulation 2006: Inappropriate shock 20% 4 shocks/patient High incidence of adverse events from ICD in Brugada syndrome. Porres, PACE 2004 Value of EPS in Asymptomatic Brugada Syndrome Brugada series Other studies Asympt 263 EPS EPS+ 35% VF 12% EPS - 65% 1% Asympt 457 EPS EPS+ 20% EPS- 80% VF 4% 2% Asymptomatic A Meta-Analysis patients of Worldwide with inducible Published VF Data. =198 M. patients Paul. Eur from Heart 8 J studies

12 Baseline EPS VF Total Symptomatic Asymptomatic * 23 * EPS on QND Negative (87%) 9 (90%) Long term Quinidine F-U: Years VF Expected VF by 3 years (Brugada JCE 2003): 54%, 23% and 12% for patients *Cardiac presenting arrest with = cardiac, 7, syncope syncope = 7 or asymptomatic *Vasovagal with inducible syncope VF, = 1respectively. Quinidine works well in the web-preparation: Prevention of phase-2 reentry by quinidine in the model of Brugada syndrome (Yan, Antzelevitch 2006) 12

13 Quinidine works well in the real world: Efficacy of Quinidine in High-Risk Patients with Brugada Syndrome Quinidine works well in EP-laboratory: Baseline: Induction of VF with 2 extrastimuli A1 A2 A2 A3 A4 A5 A6 A7 A8 A9 A10 A12 A11 Quinidine 1.5 g/day: No inducible arrhythmias with 4 extrastimuli A13 A14 B1 B2 B3 B4 B5 B6 B7 B9 B10 Belhassen, Glick, Viskin Circulation Belhassen, Circulation

14 QT interval duration predicts outcome in LQTS Quartiles: <446 msec >499 msec 193 families 647 affected patients LQT1 commonest This is not a benign condition <50% mutation carriers have events Priori et al 2003 Priori et al 2003 Relative risk of arrhythmic events in patients with Brugada ECG and positive EPS Kanda (2002) Priori (2002) Brugada (2003) Morita (2003) Mok (2004) Ekardt (2005) Summary (2006) lower risk for EP Relative risk Gehi: Risk stratification in Brugada syndrome, a Meta-Analysis. JCE No risk for EP Higher risk for EP+ Dear Sami, Regarding beta-blockers for LQT1 and LQT2, the general philosophy that beta-blockers should be routinely administered as prophylactic therapy to prevent SCD as a first event is reasonable. In our 1998 NEJM article (attached), the incidence of LQTS-related SCD as a first event from birth through the age of 40 years was 1-2% for LQT1/LQT2, and about 3% for LQT3 (see Table 3). As a specialist in LQTS, it is clear that some LQTS patients are at very low risk for cardiac events, for example, LQT2 males over 20 years with QTc <0.48s. The incidence of SCD as a first event is this subgroup might be as low as 0.1% over 40 years. As you know, beta-blockers only reduce the risk of cardiac events and SCD by about 75%, but they are not 100% successful in preventing such events. For an analogy, you might want to draw on the recent revision of routine 2-day prophylactic antibiotics for dental work in patients with a heart murmur. The current recommendation is to provide prophylaxis only for high-risk patients, and here we are talking about just 2 days of antibiotics. As a fellow musketeer, I leave it to you to work out the prophylactic beta-blocker recommendation for LQTS patients. 14

15 Role of Programmed Ventricular Stimulation in Patients with Brugada Syndrome. A Meta-Analysis of Worldwide Published Data. M. Paul, J. Gerss, E. Schulze-Bahr, T. Wichter, C. Vahlhaus, A.A.M. Wilde, G. Breithardt, L. Eckardt. Eur Heart J 2007 (In Press). Inducible VF (%) What percentage of patients with Brugada syndrome have inducible VF? Brugada series Cardiac arrest P<0.001 P<0.001 Asymptomatic All the others Cardiac arrest Asymptomatic Role of Programmed Ventricular Stimulation in Patients with Brugada Syndrome. A Meta-Analysis of Worldwide Published Data. M. Paul, J. Gerss, E. Schulze-Bahr, T. Wichter, C. Vahlhaus, A.A.M. Wilde, G. Breithardt, L. Eckardt. Eur Heart J 2007 (In Press). Brugada (2003) 15 Other studies Number of patients with Brugada syndrome who underwent EPS % 23% % % % % 774 Cardiac arrest Syncope Asymptomatic Patients included in different series of Brugada syndrome: Same but different?. Male Type I ECG Brugada (2003) n= 443 Bordachar (2004) n= 59 Priori (2002) n= 200 Eckardt (2005) n= % 75% 76% 72% 71% 83% 51% 59% Months % with events 14% 5% 7% 4% 1 2 Higher inducibility rates in the Brugada Series: Sicker patients? Aggressive EP protocol? More pacing sites? More extrastimuli? Shorter coupling intervals? 15

16 Contribution of the RVOT (right ventricular outflow tract) to inducibility of VF. VF inductions. Inducible from RVA Inducible from RVOT Total = 144 patients with inducible VF RVA 43% RVOT 56% Higher inducibility rates in the Brugada Series: Not due to aggressive EPS protocol. Pacing Sites Brugada series RVA only Other studies RVA + RVOT Extrastimuli 3 3 Minimal coupling interval 200 ms 200 ms Eckardt (Eur Heart J 2002): 66% of VF episodes in Brugada were induced with CI < 200 msec So.. patients in the Brugada Series are more inducible.. it MUST be the patients let's look again at the data 45 patients with Brugada syndrome (all type I) ECG. All patients underwent EP-stimulation at all sites. Inducible VF in 17 (38%) patients (Morita, JCE 2003). RVOT 100% Despite similar patient characteristics. despite less aggressive protocol LV RVA 12% RVOT Free wall RVOT Septum 16

17 What is the role of EPS in asymptomatic patients with Brugada syndrome??? % Asymptomatic Brugada patients in different publications. % All patients Asymptomatic patients Percentage of asymptomatic patients who developed arrhythmias during follow-up. 25% 20% % 5% 4% 1% 3% 15% 10% 5% Brugada 1998 Brugada 2002 Brugada 2003 Priori 2003 Eckardt 2005 Paul (meta-analysis) 2007 A Meta-Analysis of Worldwide Published Data. M. Paul. Eur Heart J 2007 (In Press). What is the false-positive rate of inducible VF? Induction of VF with 2 extrastimuli: Induction of VF with 2 extrastimuli in a healthy control Viskin, Europace 2007 RVA 52 patients 600/250/220 msec without ventricular arrhythmias: Stimulation only at the RVA. Only one basic cycle length. No minimal coupling interval. Am J Cardiol

18 Probability of arrhythmic event. The maximal QTc of repeated measurements matters most. 50% 30% 10% Maximal QTc > 500 msec Baseline QTc <500 msec Maximal and baseline QTc > 500 msec Maximal and baseline QTc < 500 msec Goldenberg, JACC