Prevention of Sudden Death in ARVC
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1 ESC Munich, August 29, 2012 Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): Prevention of Sudden Death in ARVC Thomas Wichter, MD, FESC Professor of Medicine - Cardiology Marienhospital Osnabrück Niels - Stensen Kliniken Dept. of Cardiology and Angiology Osnabrück, Germany Heart Center Osnabrück Bad Rothenfelde
2 No Conflict of Interest Nothing to Disclose with regard to this presentation
3 Arrhythmogenic RV Cardiomyopathy Aziz et al., Circulation. 2000;101; Wichter T et al. Internist. 2004:45:
4 Arrhythmogenic RV Cardiomyopathy Clinical Features Young, apparently healthy pts Ventricular arrhythmias of LBBB morphology Exercise provocable arrhythmias High prevalence in athletes Family history (ARVC, unexplained sudden death or VT) RV-enlargement or RV-dysfunction Right precordial ECG abnormalities T-wave inversion, broad S-wave upstroke QRS prolongation, Epsilon potential
5 Arrhythmogenic RV Cardiomyopathy Zhurinsky J et al. J Cell Sci 113: (2000) Disease of the Desmosome Apoptose
6 Arrhythmogenic RV Cardiomyopathy Genetic Disposition Double/compound mutations, modifier genes Autonomic Dysfunction Cell Contact Damage RV-Stretch (Exercise) Connexins Gap Junctions Desmosomes Adherens Junctions Myocardial Atrophy Fibrofatty replacement Myocarditis Ventricular Arrhythmias Heart Failure Wichter T et al. in Marcus FI, Nava A, Thiene G (eds.), Springer Verlag. 2008, page 147
7 Sudden Death as a Primary Manifestation Electrophysiological abnormalities with a risk of life-threatening arrhythmias may precede overt morphological changes and diagnostic signs. * Unresolved challenge for risk stratification and SD prevention in ARVC. Aziz et al., Circulation. 2000;101; * Gomes J, et al. Eur Heart J. 2012
8 Risk Factors for VT + Sudden Death History of cardiac arrest, sustained VT or syncope Intolerable or pleomorphic VT at EPS Nonsustained VT at exercise or Holter Severe RV dysfunction or right heart failure RV/LV Functional Imaging: Echo, Angio, MRI, (RNV) RV/LV Scar Imaging: MRI (LE), Voltage Map ECG: Depolarization and Repolarization Abnormalities - QRS-Duration / - Dispersion - Epsilon Potential or Late Potential (SAECG) - T-wave inversion beyond V2/3 LV involvement Family history (ARVC with sudden death)
9 Cardiovascular Death 21 / 130 pts (FU: 8.1 ± 7.8 yrs) no VT or CHF n=7 n=14 VT, no CHF Causes of Death 92% on AA Drugs 10 pts with ICD VT and CHF Hulot JS et al., Circulation. 2004;110:
10 Hulot JS et al., Circulation. 2004;110: Prediction of Cardiovascular Death 130 pts; follow-up 8.1 ± 7.8 yrs
11 RV and LV Dysfunction (n= 98 pts, FU 128 ± 92 mths) Ventricular dysfunction is a marker of risk (No, only RV, or RV+LV dysfunction) Pinamonti B et al. Eur Heart J. 2011
12 RV and LV Dysfunction Predictor of Cardiac Death or HTx n= 96 pts Pinamonti B et al. Eur Heart J. 2011
13 Case 1: 34 yr. old male Monomorphic sustained VT Poorly tolerated, no syncope Advanced RV disease, Early onset PKP2 stop mutation ICD implantation Maintz D, Wichter T, et al. Circulation. 2006;113:673
14 Survival Benefit from the ICD Estimate: 36% after 5 years (high-risk cohort, sec. prev.) (hypothetical death) n= 60 pts follow-up: months Wichter T et al. Circulation. 2004;109:
15 Survival VF / V-Flutter Survival Benefit from the ICD Predictors of VF / V-flutter n= 132; FU mths. Corrado D et al., Circulation 2003;108:
16 ICD Undersensing in ARVC fragmented QRS-complex, T-wave inversion extensive RV-dysfunction, atypical lead position Wichter T et al. Circulation. 2004;109:
17 Lead-related ICD complications Follow-up: 80 ± 43 (6-147) mths pts. (n=60) Event (severe) Complications Lead dislodgement Insulation defect / oversensing Lead fracture (RV) Lead fracture (subcutaneous) Lead thrombosis Undersensing Perforation n=21 (35%) n= 2 ( 3%) n=10 (17%) n= 5 ( 8%) n= 1 ( 2%) n= 2 ( 3%) n= 8 (13%) n= 0 n=31 (26) n= 2 (2) n=13 (11) n= 5 (4) n= 1 (1) n= 2 (1) n= 8 (7) n= 0 Wichter T et al. Circulation. 2004;109:
18 Case 2: 28 yr. old male Monomorphic VT, 162 bpm Well tolerated Exercise induced 1 prior episode of tachycardia No history of syncope No family history of SCD ECG: T-wave inversion V1-V3 Imaging: RV-outflow aneurysm No signs of LV involvement
19 Case 2: 28 yr. old male Wichter T et al. Card Electrophysiol Clin. 2011;3:
20 VF / V-flutter after ICD implant stable VT unstable VT syncope cardiac arrest In pts with stable VT as index event, there was rare occurrence of VF or V-flutter n= 132; FU mths. Corrado D et al., Circulation 2003;108:
21 Antiarrhythmic Drugs in ARVC Low or intermediate risk pts Follow-up: 53 ± 32 months Wichter T et al., Herz (Cardiovasc Dis). 2005;30:91-101
22 Corrado D, et al. Circulation. 2010;122:1144
23 ICD for Primary Prevention DARVIN-2 Multicenter Study Unequivocal diagnosis of ARVC (n=106) No prior history / documentation of sustained ventricular tachyarrhythmias (VT or VF) Main indication for ICD implantation: Unexplained syncope (n= 42) Asymptomatic nonsustained VT (n= 40) Family history of SD (n= 24) Follow-up >6 months after ICD implantation Corrado D, et al. Circulation. 2010;122:1144
24 ICD for Primary Prevention Patient Characteristics (n= 106) (+) (+) Corrado D et al. Circulation. 2010;122:1144
25 ICD in ARVC: Primary Prevention VF / V-flutter (n=17 / 106 pts = 16%) Estimated mortality reduction: 23% at 48 months (5.8% / yr) Overall Population Unexplained Syncope FU 58 ± 35 mths Corrado D,, Wichter T, et al. Circulation. 2010;122:1144
26 ICD in ARVC: Primary Prevention Nonsustained VT ICD Therapy for any VT ICD Therapy for VF / V-flutter FU 58 ± 35 mths Corrado D, et al. Circulation. 2010;122:1144
27 ICD in ARVC: Primary Prevention Age (early disease onset) ICD Therapy for any VT ICD Therapy for VF / V-flutter FU 58 ± 35 mths Corrado D et al. Circulation. 2010;122:1144
28 Risk Stratification in ARVC Corrado D et al. Card Electrophysiol Clin. 2011;3:
29 Management Strategy in ARVC Life-Style Changes, Discourage of Sports, Follow-up Symptomatic Asymptomatic Cardiac arrest, VF Hemodyn. unstable VT Unexplained syncope Hemodyn. stable VT nsvt, freq. PVC mod./severe RV- / LVdysfunct. Family history SD No risk factor mod./severe RV- / LVdysfunct. no yes ICD class I ICD class I ICD class I (EP +) class IIa (other) AA-Drugs class I Ablation class IIb CHF-Medication class I Antithrombotics class IIb β-blockers class IIb β-blockers (adjunct) class I ICD class IIa ICD class IIa ICD class IIb ICD class IIb
30 Conclusions Data on risk stratification for sudden death prevention in ARVC pts are rare. Most recommendations are personal or consensus (level C) and result from non-randomized (retrospective) studies or registries. Early diagnosis and identification of pts at risk of sudden death as a primary disease manifestation remain unresolved and challenging.
31 More data are needed to refine risk stratification in order to prevent sudden death in ARVC Conclusions High risk of SD: Pts after survived cardiac arrest, hemodynamically unstable VT or arrhythmic syncope should be treated by an ICD (and adjunct β-blocker) Moderate risk of SD: Pts with well tolerated VT or nsvt with moderate or severe RV / LV dysfunction should be treated by drugs to prevent recurrences may be treated by an ICD for safety back-up Low risk of SD: Pts with only PVC, family history or no risk factor may be treated by β-blockers or surveillance only
32 ESC Munich, August 29, 2012 Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): Prevention of Sudden Death in ARVC Thomas Wichter, MD, FESC Professor of Medicine - Cardiology Marienhospital Osnabrück Niels - Stensen Kliniken Dept. of Cardiology and Angiology Osnabrück, Germany Heart Center Osnabrück Bad Rothenfelde
33 PKP2 mutations and event rates no differences in clinical and arrhythmia characteristics Stop Frameshift Missense All patients 14 patients 12 patients 9 patients Duration of follow-up, years 12 ± 7 14 ± 5 10 ± 7 12 ± 10 ns Age at last follow-up, years 49 ± ± ± ± 14 ns Patients alive, n (%) 31 (89) 11 (79) 11 (92) 9 (100) ns Patients deceased, n (%) 4 (11) 3 (21) 1 (8) 0 ns Cardiac death, n (%) 2 (50) 2 (67) 0 0 ns svt/vf during follow-up, n (%) 21 (60) 11 (79) 7 (58) 2 (22) p<0.03 Time to 1 st svt/vf, years 2.4 ± ± ± ± 2.9 ns Paul M, Wichter T et al. Clin Res Cardiol (Abstr.)
34 PKP2 mutations and event rates Sustained VT or VF Missense mutation Frameshift mutation HR 4.6 (95% CI ) P < 0.04 Stop mutation Paul M, Wichter T et al. Clin Res Cardiol (Abstr.)
35 Risk Stratification in ARVC PVC count per 24 hrs Appropriate ICD therapies in primary prevention Bhonsale et al. JACC. 2011;58:
36 Risk Stratification in ARVC ICD therapies in prim. prevention PVC > 1000 / 24 hrs Proband vs. Relative Bhonsale et al. JACC. 2011;58:
37 Risk Stratification in ARVC ICD therapy for any VT (prim. prev.) Inducible VT at EPS Nonsustained VT Bhonsale et al. JACC. 2011;58:
38 Risk Stratification in ARVC VT Inducibility at EPS ICD therapy for any VT (n= 67, FU 4.4±2.9 yrs) Piccini JP et al. Heart Rhythm. 2005; 1:
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