Exercise-induced ventricular arrhythmias in CPVT patients occur at lower heart rate on beta-blocker therapy

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1 Exercise-induced ventricular arrhythmias in CPVT patients occur at lower heart rate on beta-blocker therapy Leren IS, Haugaa KH, Berge KE, Bathen J, Loennechen JP, Anfinsen OG, Früh A, Edvardsen T, Kongsgård E, Leren TP, Amlie JP Department of Cardiology/Department of Medical Genetics/Department of Pediatrics Oslo University Hospital, Rikshospitalet University of Oslo Department of Cardiology, St. Olav s Hospital Norwegian University of Science and Technology. Disclosures: None

2 Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable arrhythmogenic disease Mutations in the genes coding for Ryanodin receptor 2 or Calsequestrin 2 found in %. Disrupted regulation of calcium homeostasis Stress-induced syncopes or sudden death due to ventricular arrhythmias

3 Background Treatment is based on beta-blocker therapy and ICD (Priori et al. 2008) The antiarrhythmic mechanisms of betablockers are not fully elucidated Varying results of beta-blocker effect on arrhythmias in CPVT patients have been reported (Hayashi, Denjoy et al, Circulation Haugaa, Leren et al, Europace 2009)

4 Aim To determine the effect of beta-blocker treatment on exercise-induced arrhythmias in CPVT index patients and mutation positive family members

5 Methods 35 patients were followed 24 (8-288) months 5 CPVT index patients 30 mutation positive family members Anamnestic interview, clinical examination, echocardiography, resting ECG, signal averaging ECG and exercise-test Exercise test 1 = before start of treatment Exercise test 2 = after minimum 3 months on maximum tolerated dosage of beta-blocker

6 Methods Heart rate At rest Exercise test At maximum exercise At start of ventricular arrhythmias Ventricular premature beats / bigeminy Couplets Non sustained ventricular tachycardia Workload At start of ventricular arrhythmias

7 Results baseline Population Population (n) 35 Males (n) 20 Females (n) 15 Age (yrs) 24 (6-75)

8 Results baseline Genetic findings Mutation n G4671V 97 RyR2 8 G2337V 46 RyR2 17 R176Q 8 RyR2 2 A2387V 47 RyR2 6 F2307L 45 RyR2 1 No mutation found 1

9 Pedigree Mutation in the RyR2 gene 24 yrs 24 yrs 10 yrs 43 yrs 18 yrs 32 yrs 10 yrs 43 yrs 18 yrs 32 yrs 24 yrs 13 yrs 10 yrs Age at time of death Mutation positive Deceased

10 Results baseline CPVT-related symptoms Index patients (n=5) 2 cardiac arrests during exercise 2 syncopes 1 near drowning Family members (n=30) 8 syncopes All had normal resting ECG, echocardiography and signal averaging ECG

11 Results Exercise test 1 prior to beta-blocker treatment In 25 of 35 patients ventricular arrhythmias occurred

12 Treatment Maximum tolerated dosages of beta-blockers Beta-blocker Dosage (mg) Metoprolol (n=21) 123 ± 50 Nadolol (n=10) 77 ± 34 Bisoprolol (n=2) 10 Propranolol (n=2) 170 ± 14 Carvedilol (n=1) 25 7 patients received ICD

13 Results Exercise tests Before On P-value beta-blocker beta-blocker Resting HR 70 ± ± 14 <0.001 Maximum HR 173 ± ± 22 <0.001 First VPBs 132 ± ± Workload at first VPB (W) HR at most severe arrhythmia 121 ± ± ± ± HR = heart rate, VPB = ventricular premature beat

14 Before beta-blocker Results Exercise tests RR =440ms / 136 bpm On beta-blocker RR =490 ms / 122 bpm

15 Results Exercise tests Before beta-blocker On beta-blocker VPBs / bigeminy (n) ns Couplets (n) 5 4 ns P-value nsvt (n) VPB = ventricular premature beat, nsvt = non sustained ventricular tachycardia

16 Results Effect of beta-blocker treatment on exercise-induced arrhythmias Arrhythmia suppressed Less severe arrhythmia % of patients 8 20 No effect 52 More severe arrhythmia 20

17 Summary Exercise-induced arrhythmias occurred at lower heart rate on beta-blockers than untreated Workload at the occurrence of arrhythmias remained unchanged Beta-blocker therapy suppressed exerciseinduced VPB in only two patients Beta-blocker therapy suppressed exerciseinduced nsvt in 4 of 6 patients

18 Conclusions In patients with CPVT, beta-blockers appeared to suppress nsvt, while less severe arrhythmias were not affected Beta-blocker treatment lowered the heart rate threshold for exercise-induced arrhythmias The protective effects of beta-blockers may not be due to negative chronotropy alone

19 Results exercise test, family members Before After P-value beta-blocker beta-blocker Resting HR 70 ± ± 13 <0.001 Maximum HR 173 ± ± 22 <0.001 First VPBs 135 ± ± Workload at first VPB (W) HR at most severe arrhythmia 121 ± ± ± ± 21 <0.01 HR = heart rate, VPB = ventricular premature beat

20 Results exercise test, index patients Before beta-blocker After beta-blocker Resting HR 77 ± 9 74 ± 26 Maximum HR 181 ± ± 28 First VPBs 106 ± ± 44 HR = heart rate, VPB = ventricular premature beat

21 Results Exercise test 1 Exercise-induced arrhythmias were present in 25 patients Index patients Family members No arrhythmias (n) VPBs (n) Total Bigeminy (n) Couplets (n) nsvt (n) VPB = ventricular premature beat, nsvt = non sustained ventricular tachycardia

22 Results Exercise test 1 and 2 Index patients Exercise test 1 Exercise test 2 No arrhythmias (n) 2 0 VPBs (n) 1 1 Bigeminy (n) 0 1 Couplets (n) 0 0 nsvt (n) 1 1 VPB = ventricular premature beat, nsvt = non sustained ventricular tachycardia

23 Results Exercise test 1 and 2 Family members Exercise test 1 Exercise test 2 No arrhythmias (n) 6 3 VPBs (n) 1 5 Bigeminy (n) Couplets (n) 5 4 nsvt (n) 5 1 VPB = ventricular premature beat, nsvt = non sustained ventricular tachycardia