What is New in CPVT? Diagnosis Genetics Arrhythmia Mechanism Treatment. Andreas Pflaumer

Transcription

1 What is New in CPVT? Diagnosis Genetics Arrhythmia Mechanism Treatment Andreas Pflaumer

2 Diagnosis of CPVT Induction of different types of VES or VT by exercise or catecholamines AND exclusion of of other diseases

3 Syncope and CPVT Exertion is the most frequent trigger emotional stress and normal activity are also reported Roston TM, Vinocur JM, Maginot KR, et al. Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol 2015;8:

4 Case C.M., male 12y, one week abdominal pain, weak, now vomiting and poor perfusion

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6 10 min after Cardioversion

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12 More atrial foci in the LA, cavotricuspid flutter line Ongoing atrial tachycardia on VAD Flecainide + Carvedilol high dose VAD Explant after 10 months

13 CPVT? RYR2 variant - not previously described NM_ (RYR2):c.14570T>A; p.(ile4857asn), first classified as a VUS, suspected somatic Mosaicism `

14 Differential Diagnosis CPVT Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and other CMP LQT 7 (Andersen-Tawil Syndrome) WPW (subtle) Brugada Syndrome Coronary Disease

15 Jadhav M et al. Anomalous Aortic Origin of the Left Coronary Artery From the Right Coronary Sinus: Diagnosis and Surgical Repair of Intramural Retrovalvular Coronary Artery. Ann Thorac Surg 2015;100:

16 CPVT Associated Genes Ryanodine Receptor Type-2 (RyR2) Macromolecular Complex. Andrew P. Landstrom et al. Circ Res. 2017;120:

17 Genes linked to genetic arrhythmia disorders Yellow fill indicates gene that encodes a Ca2+-sensitive or Ca2+handling protein. Andrew P. Landstrom et al. Circ Res. 2017;120:

18 Risk Stratification in CPVT No genetic/mutation specific markers? No clinical markers? Medical treatment for all patients with genetic or clinical diagnosis Holter and Exercise test to estimate effectiveness of therapy?

19 Abstract HRS May 2018 B-AB02-06 Pathogenicity of new mutations Mapping of 250 mutations on Cryo- Electron Microscopy Structure Engineering and testing some oft these seemed to identify mutations in critical regions functionally relevant

20 Events Circadian Influence? Miyake, C. Y., et al. (2017). Circadian Variation of Ventricular Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia. JACC: Clinical Electrophysiology, 3(11),

21 Risk of Relatives of RYR2 index patients Broendberg, A. K.et al. (2017). Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. British Heart Journal, 103(12),

22 Rate Of Heart Rate Reduction After Exercise Is A Useful Tool For Risk Stratification In Catecholaminergic Polymorphic Ventricular Tachycardia HRS 2018, Abstract HRS B-PO05-146, Krystien Lieve et al.

23 Therapy Recommendations 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm,

24 Nadolol vs other Beta Blocker Leren, I. S. et al (2016). Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm, Volume 3, Issue 5, Supplement, Page S135, May 2006, 13(2),

25 Flecainide and CPVT Kannankeril PJ, Moore JP, Cerrone M, et al. Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial. JAMA Cardiol Published Online First: 10 May 2017.

26 Sympathectomy and CPVT De Ferrari GM, Dusi V, Spazzolini C, et al. Clinical Management of Catecholaminergic Polymorphic Ventricular Tachycardia: The Role of Left Cardiac Sympathetic Denervation. Circulation 2015;131:

27 Side Effects of Symphatecto my Seshadri Balaji Physical and Psychological Consequences of Left Cardiac Sympathetic Denervation in Long-QT Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia: Kathryn E. Waddell-Smith,et al., Circulation: Arrhythmia and Electrophysiology. 2015;8:

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29 ICD Benefit versus Harm Olde Nordkamp LRA, Postema PG, Knops RE, et al. Implantable cardioverter-defibrillator harm in young patients with inherited arrhythmia syndromes: A systematic review and meta-analysis of inappropriate shocks and complications. Heart Rhythm Journal 2016;13:443 54

30 Lieve et. al, B-PO02-058, HRS 2018 ICD For Secondary Prevention Of Sudden Cardiac Death In CPVT Retrospective study with 115 CPVT patients, 66 having an ICD implanted after ACA, 5 year follow up 1 death, 3 ACA in the non ICD group In the ICD group 40% experienced appropriate shocks, 22% inappropriate shocks and 30% ICD complications

31 Cardiac Optogenetics Boyle, P. M., Karathanos, T. V., & Trayanova, N. A. (2018). Cardiac Optogenetics: JACC: Clinical Electrophysiology, 4(2), \

32 Mitochondrial Calcium Uptake Enhancers

33 Viral Delivered Gene Therapy Intracardiac (A) vs peritoneal (B) injection Effective if 33% protein expression Calsequestrin 2, mouse model Kurtzwald-Josefson, et al. (2017). Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models. Heart Rhythm 14(7),

34 Allele-Specific Silencing of Mutant mrna Using adeno-associated virus-mediated RNA SR casq2 Bongianino, et al. (2017). Allele-Specific Silencing of Mutant mrna Rescues Ultrastructural and Arrhythmic Phenotype in Mice Carriers of the R4496C Mutation in the Ryanodine Receptor Gene (RYR2). Circulation Research, 121(5),

35 CPVT what we know now Consider CPVT in your differential diagnosis Negative genetic finding does not exclude it Presentation is frequently Syncope/VT/Arrest Though can present with atrial tachycardia and atrial fibrillation Treatment with beta blocker + flecainide, add sympathectomy and avoid ICD

36 CPVT what is coming up Overlap Syndromes with other diseases caused by Ca++ regulation disorders Gene / Channel specific medical therapy Gene modification / Silencing of mutant mrna Optogenetic Therapy

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