J-wave syndromes: update on ventricular fibrillation mechanisms

Transcription

1 J-wave syndromes: update on ventricular fibrillation mechanisms Michael Nabauer University of Munich, Germany

2 I have no conflicts of interest

3 ECG labelling by Einthoven Circ 1998

4 Osborn wave in Hypothermia 23 dog John J. Osborn, AJP 1953

5 Definition of Early Repolarisation / J-wave Syndrome early repolarisation syndrome (ERS) is an ECG signature at the terminal downslope of the QRS-complex two different morphological variants of this phenomen exist: - slurring of the terminal ORS-complex - notch / J-wave following the QRS-complex at least 2 leads (except avr, V1-3) amplitude of at least 0.1 mv in each lead Haissaguerre et al. (NEJM 2008)

6 Early Repolarization Pattern Miyazaki, Haissaguerre M, Circ J 2010

7 Early Repolarization: a Marker of VT/VF Increased prevalence in 206 patients with IVF as compared to 415 controls (31% vs. 5%, p<0.001) IVF-patients with early repolarization pattern are more likely to have recurrent episodes HR 2,1 (1,2-3,5), p=0.008 More likely to be Male More likely to have syncope or cardiac arrest during sleep Increased amplitude is associated with increased risk Haissaguerre M et al., NEJM 2008;358:

8 Clinical and therapeutic data in 16 patients with electrical storm and Early Repolarization pattern Haissaguerre M, et al., J Am Coll Cardiol 2009

9 Acute Therapy of VT/VF Storm in Early Repolarization Syndrome with Isoproterenol Multiple episodes of VF and correction by i.v. iso. Normalization of QRST morphology by i.v. isoproterenol Haissaguerre M, et al., J Am Coll Cardiol 2009

10 Ablation of Early Repolarization Pattern with Quinidine 42 y, m, 36 episodes of VF during 24 months FU 42 y, m, event free during 18 months FU w chinidine 600 mg/d hydrochinidine Haissaguerre M, et al., J Am Coll Cardiol 2009

11 SCD Syndromes involving Early Repolarisation Benito, Guasch, Rivard, Nattel, JACC 2010

12 Cellular basis for the electrocardiographic J wave in hypothermia Dog LV Yan, Antzelevitch. Cellular basis for the electrocardiographic J wave. Circ 1996

13 J-wave pattern and arrhythmogensis Two major pathophysiological mechanisms proposed 1. Depolarisation abnormalities Slowed conduction with delayed epiardial activation with repolarisation abnormalities being secondary (mild) structural abnormalities 2. Primary repolarisation abnormality Dispersion of repolarisation between endocardium and epicardium

14 Depolarisation abnormality Meregalli, Cardiovasc Res 2005

15 Depolarisation abnormality Support some studies (body surface mapping, epicardial/ endocardial mapping) show delayed activation conduction delay more pronounced after Na-channel block late potentials as manifestation of delayed and discontinous depolarisation structural abnormalities not infrequently reported Fibrosis on biopsy Frequent structural and functional abnormalities (Papavassiliu,..Borggrefe, HR 2010; Catalano,..Priori EHJ 2009) Difficult to explain Beneficial effect to Quinidine Beneficial effect of increased frequency

16 Repolarisation abnormality Human LV myocyte Ito IKATP 0 mv INa ICa ms APD Antzelevitch, 1991

17 Ito activation is arrhythmogenic (NS5806; dog wedge) Calloe.. Antzelevitch, CVR 2009

18 Repolarisation abnormality Antzelevitch, 1991, 2004

19 Transmural electrical heterogeneity of Ito in human left ventricular myocardium Endocard Epicard Epi central 12 Human myocardium Stromdichte density pa/pf Ito pa/pf mm subendo Epikard Mitte Endokard Endo 10 pa/pf

20 Repolarisation abnormality Support experimental model (perfused canine wedge) Na-channel block induces Type 1 Brugada ECG (ICa block, increase Ito, IKATP) increased frequency and isopoterenol are beneficial beneficial effect of Quinidine (Ito block) delayed activation in RV-OT not a regular finding in BrS unifying hypothesis for early repolarisation, explains arrhythmogenicity in structurally normal heart provides substrate and trigger Questions how to explain late potentials feasibility in the intact heart (prevented by tight coupling?) gene defects only in about 20-30% and would affect the whole heart Requirement for some additional pathology for local manifestation?

21 Ito differences dog human LV Human epicardial Dog epicardial 100 ms 1 na 100 ms 1 na Recovery I/Imax I to t = ms, n=10 human epicardial dog epicardial Interpulse intervall [s] Data at 23 at T = 35 Recovery ~3.7 fold faster : :17 D:Origin_ProjectsOld :17 D:Origin_ProjectsOld Näbauer et al., Circulation 93:168 (1996)

22 Ito differences dog human LV Human epicardial Dog epicardial 100 ms 1 na 100 ms 1 na Recovery I/Imax I to t = ms, n=12 t = ms, n=10 human epicardial dog epicardial Interpulse intervall [s] Data at 23 at T = 35 Recovery ~3.7 fold faster : :17 D:Origin_ProjectsOld :17 D:Origin_ProjectsOld Näbauer et al., Circulation 93:168 (1996)

23 Elevation of phase 1 and 2 at 2 Hz in human LV epicardial action potential Näbauer et al., Circulation 93:168 (1996) Näbauer et al., Circulation 93:168 (1996)

24 Currently, different viewpoints on the mechanisms (primary depolarisation vs repolarisation abnormality) supported by divergent evidence. Possibly different mechanisms dominant in different disease variants with a similar ECG phenotype

25 Do BrS and ERS share identical pathophysiological mechanisms just at different localisations?

26 Antzelevitch, Heart Rhythm 2010

27 ERS: Response to Na-channel block Twelve-lead ECGs in a patient with Brugada syndrome under baseline conditions (A) and after pilsicainide administration (B). ER was seen in inferior (II, III, avf) and lateral (V4-V6) leads under baseline conditions (A, arrows). Intravenous administration of 30 mg of pilsicainide unmasked coved type Brugada ECG and remarkably augmented the J-point and ST-segment in the right precordial leads (V1-V3) (B, dashed arrows), while ER was attenuated in inferior and lateral leads (B, arrows). Kawata, Heart Rhythm 2010, in press

28 Understanding the pathophysiology of arrhythmic SCD syndromes is essential to identify any underlying disease and initiate treatment improve antiarrhythmic drug treatment to enable better risk stratification for sudden death to initiate preventive treatment