Παναγιώτης Ιωαννίδης. Διευθυντής Τμήματος Αρρυθμιών & Επεμβατικής Ηλεκτροφυσιολογίας Βιοκλινικής Αθηνών

Transcription

1 Διαστρωμάτωση κινδύνου για αιφνίδιο καρδιακό θάνατο σε ασθενείς που δεν συμπεριλαμβάνονται σε μεγάλες κλινικές μελέτες «Ασθενείς με ηλεκτρικά νοσήματα» Παναγιώτης Ιωαννίδης Διευθυντής Τμήματος Αρρυθμιών & Επεμβατικής Ηλεκτροφυσιολογίας Βιοκλινικής Αθηνών 36ο Πανελλήνιο Καρδιολογικό Συνέδριο Θεσσαλονίκη,

2 Agenda Long QT Syndrome Short QT Syndrome Catecholaminergic polymorphic ventricular tachycardia (CPVT) Brugada Syndrome Early Repolarization Syndrome Disorders responsible for 10% 15% of cases of sudden unexplained death in young adults and children1 1 Deo et al. Circulation. 2012;125:

3 Long QT Syndrome (LQTS) Prolonged Repolarization Prolonged QT Torsades de pointes

4 QT Interval: What Is Normal? The QT interval should be measured preferentially in leads II or V5 Cowan et al. Am J Cardiol. 1988;61:83-7 Bazett s formula: QTc=QT/ RR (expressed in seconds) Bazett H. Heart. 1920;7: Although a QTc interval of 440 ms in males and 460 ms in females is considered abnormal, one can find carriers of mutations as well as healthy individuals within this range

5 LQTS: Diagnostic Score Schwartz et al. Circulation 1993;88: Schwartz et al. Circulation 2011;124:

6 Diagnosis of Long QT Syndrome 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

7 LQTS patients may have QTc values within normal limits Serial ECG testing or acquisition of previous ECGs Holter monitoring Priori ESC Congress London 2015

8 Long QT syndrome by genetic subtype LQTS subtype LQT1 LQT2 Culprit gene KCNQ1 KCNH2 Protein Functional effect of mutation Alpha-subunit of IKs Loss-of-function, reduced IKs Alpha-subunit of IKr Loss-of-function, reduced IKr LQT3 SCN5A Alpha-subunit of INa 5 10 LQT4 ANK2 LQT5 KCNE1 Ankyrin-B; links membrane proteins with underlying cytoskeleton Beta-subunit of IKs Gain-of-function, increased late INainward current Loss-of-function, disrupts multiple ion channels Loss-of-function, reduced IKs <1 LQT6 KCNE2 Beta-subunit of IKr Loss-of-function, reduced IKr <1 LQT7 KCNJ2 Alpha-subunit of IKl Loss-of-function, reduced IK1 <1 LQT8 CACNA1c Alpha-subunit of ICaL Gain-of-function, increased ICaL Rare LQT9 CAV34 LQT10 SCN4B LQT11 AKAP9 LQT12 SNTA1 LQT13 KCNJ5 Kir 3.4 Loss-of-function, reduced IKACh Rare LQT14 LQT15 CALM1 CALM2 Calmodulin-1 Altered calcium signaling Calmodulin-2 Altered calcium signaling <1 <1 Caveolin-3; a scaffolding protein in Increased late INa inward current caveolae Beta 4-subunit of INa Gain-of-function, increased late INainward current A kinase-anchor protein-9; Loss-of-function, reduced IKs sympathetic IKs activation Alpha1-syntrophin; regulation of INa Increased late INa inward current Frequency (%) <1 <1 Rare Rare Rare

9 Long QT syndrome by genetic subtype LQTS subtype LQT1 LQT2 Culprit gene KCNQ1 KCNH2 Protein Functional effect of mutation Alpha-subunit of IKs Loss-of-function, reduced IKs Alpha-subunit of IKr Loss-of-function, reduced IKr LQT3 SCN5A Alpha-subunit of INa 5 10 LQT4 ANK2 LQT5 KCNE1 Ankyrin-B; links membrane proteins with underlying cytoskeleton Beta-subunit of IKs Gain-of-function, increased late INainward current Loss-of-function, disrupts multiple ion channels Loss-of-function, reduced IKs <1 LQT6 KCNE2 Beta-subunit of IKr Loss-of-function, reduced IKr <1 LQT7 KCNJ2 Alpha-subunit of IKl Loss-of-function, reduced IK1 <1 LQT8 CACNA1c Alpha-subunit of ICaL Gain-of-function, increased ICaL Rare LQT9 CAV34 LQT10 SCN4B LQT11 AKAP9 LQT12 SNTA1 LQT13 KCNJ5 Kir 3.4 Loss-of-function, reduced IKACh Rare LQT14 LQT15 CALM1 CALM2 Calmodulin-1 Altered calcium signaling Calmodulin-2 Altered calcium signaling <1 <1 Caveolin-3; a scaffolding protein in Increased late INa inward current caveolae Beta 4-subunit of INa Gain-of-function, increased late INainward current A kinase-anchor protein-9; Loss-of-function, reduced IKs sympathetic IKs activation Alpha1-syntrophin; regulation of INa Increased late INa inward current Frequency (%) <1 <1 Rare Rare Rare

10 Genotype-phenotype correlation in the most frequent Long QT syndromes LQTS subtype LQT1 LQT2 LQT3 Current I I I Ks Kr Na Functional Effect Frequency Among LQTS 30%-35% 25%-30% 5%-10% ECG Triggers Lethal Cardiac Event Phenotype Penetrance Exercise (68%) Emotional Stress (14%) Sleep, Repose (9%) Others (19%) 62% Exercise (29%) Emotional Stress (49%) Sleep, Repose (22%) Exercise (4%) Emotional Stress (12%) Sleep, Repose (64%) Others (20%) 75% 90%

11 controls concealed LQT1 concealed LQT2 Nearly 40% of patients with long QT syndrome can have a nondiagnostic QTc at rest Horner et al. Heart Rhythm 2011;8:

12 Event-free survival according to QTc 1st quartile QTc 446 ms 2nd quartile QTc: ms 3rd quartile QTc: ms The difference among the 4th quartile QTc >498 ms quartiles was significant (P<0.001). Priori et al. N Engl J Med 2003;348:

13 Survival according to genotype Priori et al. N Engl J Med 2003;348:

14 Gender and risk stratification in LQT1 Gender effect in LQT1 Asymptomatic LQT1 male patients who have remained asymptomatic until age 15 have a lower probability of experiencing a first cardiac event. Locati et al. Circulation 1998;97:

15 Specific mutation positions herald greater risk LQT1: KCNQ1 C-loop regions Barsheshet et al. Circulation 2012;125:

16 Specific mutation positions herald greater risk LQT2: KCNH2 PORE region Males vs Females Males: Pore vs Non-pore Females: Pore vs Non-pore Migdalovich et al. Heart Rhythm 2011;8:

17 LQTS Management: beta-blockers Moss et al. Circulation 2000;101:

18 Emerging therapies for LQTS: Sodium channel blockers for LQT3 Before Mexiletine After Mexiletine 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

19 Cardiac Events in genotyped LQTS Patients Treated With β-blockers Priori et al. JAMA 2004;292:

20 LQTS: Implantable Cardioverter Defibrillator 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

21 Lifestyle modifications in Long QT Syndrome (class I): May they be the only approach in asymptomatic LQTS? Avoidance of QT prolonging drugs: Correction of electrolyte abnormalities: Avoidance of genotypespecific triggers for arrhythmias:

22 Short QT Syndrome A rare condition Male preponderance (75%) Median age of symptom onset 21 years PQ segment depression is frequently seen in SQTS Tülümen et al. Heart Rhythm 2014;11:

23 Short QT Syndrome: Diagnosis 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

24 Short QT syndrome by genetic subtype

25 Diagnostic Scoring System for Short QT Syndrome High-probability SQTS 4 points Intermediate-probability SQTS= 3 points Low-probability SQTS, 2 points *A minimum of 1 point must be obtained in the electrocardiographic section in order to obtain additional points Gollob et al. JACC 2011;57: Villafane et al. JACC 2013;61:

26 Short QT Syndrome: Management 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29 SQTS is HIGHLY LETHAL Patients who survived a cardiac arrest (n=14) had a significantly higher risk of recurrences as compared to asymptomatic (n=14) (Hazard Ratio: 37.5) Mazzanti et al. JACC 2014;63:

27 Short QT syndrome: Pharmacological Therapy? Basal Quinidine 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29 Gaita et al. J Am Coll Cardiol. 2004;43:

28 SQTS: Risk Stratification? 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29 EPS sensitivity was only 37%, and its negative predictive value was 58%. Giustetto et al. 2011;58:587-95

29 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) CPVT by genetic subtype

30 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Arrhythmic manifestations PVCs, Bidirectional VT Onset of VAs with physical exercise, emotional stress, or catecholamine administration, in the absence of structural heart disease Symptoms typically begin in childhood or adolescence, but there are cases with onset in adulthood Syncope during exercise is typically the presenting symptom Untreated, this condition has very high mortality, with reports of up to 50% by the age of 30 years TdP

31 Management of CPVT: β-blockers in all patients!!! Prefer beta-blockers without intrinsic sympathomimetic activity (nadolol, propranolol). Full dose (e.g. nadolol 1-2 mg/kg per day) Recommend strict compliance to therapy 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

32 Emerging therapies for CPVT: Sodium channel blockers 29 patients: 22/29 (76%) had arrhythmias suppression in comparison with conventional therapy. During 20 months of follow-up, only 1/29 patients had an ICD shock (low flecainide levels) van der Werf et al. JACC 2011;57: ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

33 Management of CPVT: ICDs ICD should be programmed with long delays before shock delivery to avoid painful shocks that might trigger further arrhythmias ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

34 Brugada Syndrome Type 1 ST-segment elevation spontaneously or after sodium channel blocking agent in at least one right precordial leads (V1 and V2) in a standard or a superior position (up to the 2nd intercostal space)

35 Brugada ECG: Deferential Diagnosis Type 1 (Coved type).. Type 2 (Saddleback).... Corrado et al. Eur Heart J 2010;31: Bayés de Luna et al. Journal of Electrocardiology 2102;45:

36 Risk Stratification in Brugada Syndrome (BrS) Eckardt et al. Circulation. 2005;111:

37 EP or not EP? Brugada et al. Circulation 2003;108: Consensus Conference. Circulation 2005;111:

38 EP or not EP? Paul et al. European Heart Journal 2007;28: ACC/AHA/ESC Guidelines for Management of Pts With VAs and the Prevention of SCD. Circulation 2006;114:e385-e484

39 Priori et al. JACC 2012;59:37-45

40 Priori et al. JACC 2012;59:37-45

41 Novel markers of risk in BrS Rollin et al. Heart Rhythm 2013;10:

42 Novel markers of risk in BrS Tokioka et al. JACC 2014;63:2131-8

43 Novel markers of risk in BrS Makimoto et al. JACC 2010;56:

44 SCN5A mutation do not predict the arrhythmic risk in Brugada syndrome Probst et al. Circulation 2010;121:

45 ICD in Brugada syndrome: Evolution over time At 10 years, rates of inappropriate shock and lead failure were 37% and 29%, respectively Sacher et al. Circulation 2013;128:

46 Is an appropriate ICD shock a surrogate of SCD?

47 Is an appropriate ICD shock a surrogate of SCD? Probably not! Delise et al. Heart Rhythm 2014;11: PRELUDE study: In 126 patients with +EPS all events occurred in patients with ICD (5 of 98 vs 0 of 28; P=0.58) while in182 patients with EPS major events occurred in 20% (8 of 39) of the patients with ICD and only in 0.6% (1 of 143) of those with out an ICD (P=0.0001) Priori et al JACC 2012;59:37-45

48 BrS: Implantable Cardioverter Defibrillator The only treatment able to reduce the risk of SCD in Brugada syndrome is the ICD Who does need it? 2015 ESC Guidelines for management of pts with VAs & prevention of SCD. Europace 2015 Aug 29

49 Early Repolarization Malignant Benign

50 Early Repolarization Syndrome Malignant

51 Haïssaguerre et al NEJM 2008;358:

52 10,864 pts!!! ECGs & Data from to 2007!!! Tikkanen et al Circulation 2011;123:

53 Acute Ischemia and Early Repolarization Acute Ischemia Repolarization dispersion Action potential duration Action Potentials Naruse et al. Circ AE 2012;5: Endo Rudic et al. Heart Rhythm 2012;9: Epi ECG Patel et al. Am J Cardiol 2012;110: Presence of early repolarization on admission electrocardiography is associated with long-term mortality and MACE in patients with STEMI undergoing primary percutaneous intervention Ozcan KS, Güngör B, Tatlısu MA, Osmonov D, Ekmekc i A, Calık AN, Aru garslan E, Zengin A, Bolca O, Eren M, Erdinler I. Ozcan et al. J Cardiol 2014;64:164 70

54 Some thoughts The first step in risk stratification is diagnosis Asymptomatic patients with electrical diseases are in low risk, but are the majority of the cases Every patient is asymptomatic.until he/she experiences the first event (which may be a cardiac arrest!). Decision on required therapy should be made with the patient discussing the individual risk profile

55 Ευχαριστώ για την προσοχή σας!