SEMINAIRES IRIS. Sudden cardiac death in the adult. Gian Battista Chierchia. Heart Rhythm Management Center, UZ Brussel. 20% 25% Cancers !

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1 Sudden cardiac death in the adult Gian Battista Chierchia. Heart Rhythm Management Center, UZ Brussel.! " # $ % Cancers National Vital Statistics Report, Vol 49 (11), Oct. 12, % 25% State-specific mortality from sudden cardiac death United States MMWR. 2002;51:

2 Stroke 1 Lung Cancer 2 Breast Cancer 2 AIDS 3 163, ,200 40,000 18,000 1 American Heart Association. Heart Disease and Stroke Statistics 2005 Update 2 Jemel A. CA Cancer J Clin. 2003; 53: U.S. HIV & AIDS Statistic Summary. Avert.org VT 62% SCD claims more lives each year than these other causes of mortality. 335,000 SCD 3 Torsades de Pointes 13% Bradycardia 17% Primary VF 8%! "#$#%&'(# 2

3 Sudden cardiac death in the adult Definition Epidemiology Age-related distribution Structural and electrical basis Prevention and treatment Definition Sudden cardiac death is a natural and unexpected death caused by cardiac causes that occurs within one hour of onset of symptoms. In the adult population, the most common cause of sudden cardiac death is an acute myocardial infarction leading to ventricular fibrillation. However congenital syndromes such as WPW or channelopathies can also potentially lead to lethal events. 3

4 Epidemiology. 10 Relative risk of annual SCD depending on age. Incidence per Acute ischemia 0 Inherited disorders Causes of sudden cardiac death in the adult(1) Aquired 1 Ischemic cardiomyopathy 2 Idiopathic Dilated cardiomyopathy 3 Dilated cardiomyopathy of various causes 4

5 Causes of sudden cardiac death in the adult(2) Organic heart disease 1. Myocardial: HCM, ARVD 2. Familial dilated cardiomyopathy 3. Coronary malformations 4. Congenital disease (Fallot, single ventricle, tricuspid atresia, non-corrected transposition) Causes of sudden cardiac death in the adult(3) Primary electrical diseases: 1. WPW syndrome 2. Long QT syndrome 3. Brugada syndrome 4. Cathecolamine-induced VT 5. Short coupled TdP 6. Short QT syndrome 5

6 )* + *, -./ *0* -.1./*0*-. ' Probability of Survival ICD P = OMT No. at Risk Survival (Year) OMT ICD Kadish A. NEJM 2004; 350:

7 2 3!0.")455(%(4'44(& 2) *- SCD-Heft 4(4 60*)789$:;*)78(4:;< /.=(:<0>!**8&5:; ***85:; )6'9( 7

8 !/-!/-'),1, Hazard Ratio (97.5% Cl) P-Value 0.4 Amiodarone vs. Placebo 1.06 ( ) 0.53 ICD vs. Placebo 0.77 ( ) Mortality Rate No. at Risk Months of Follow-Up Amiodarone Placebo ICD Bardy GH. NEJM 2005; 352: Amiodarone Placebo ICD,..,,!>-!)*,.,, !" " )7 6 8

9 % SCD victims #$%$&' $%$&'! $ & (' ) LVEF and incidence of SCD 7.5% 0-30% 31-40% 41-50% >50% LVEF Gorgels PMA. Eur Heart J 2003; 24: % 2.8% 1.4% 9

10 Hypertrophic cardiomyopathy 1) Prevalence1/500 2) Most common genetic cardiovascular disorder 3) Myocyte hypertrophy, disarray and interstitial fibrosis 4)More than 400 mutations of 11 sarcomeric genes 5) B-Myosin heavy chain (30-40%),cardiac troponin T and cardiac troponin I Pharmacological Therapeutic approach Septum alcoholisation Myectomy Dual chamber PM AICD 10

11 Arrythmogenic right ventricular dysplasia(1) Progressive loss of myocytes Replacement of myocardium by fatty or fibrofatty tissue from the epicardium to endocardium Autosomal dominant inheritance Most common mutations affecting desmosomal proteins and cardiac ryanodine receptor Arrythmogenic right ventricular dysplasia(2) Clinical: Syncope, Palpitations due to LBBB morphology ventricular tachycardia Echocardiographical(2D) NMR 11

12 Arrythmogenic right ventricular dysplasia(3) Sotalol Surgical approach: isolation of the fibrofatty area Catheter ablation AICD Familial dilated cardiomyopathy Up to 35% of Idiopathic DCM is familial LV dilatation, reduction of wall thickness and EF reduction Mutation of sarcolemmic and cytoskeleton proteins Autosomic dominant X-linked 12

13 Familial dilated cardiomyopathy The therapeutical approach is the approach to heart failure. In young patients consider heart transplantation. Primary electrical diseases 13

14 Wolff-Parkinson-White Fast and slow accessory AV pathway 14

15 Atrial fibrillation Ventricular fibrillation (VF) EPS and cure of WPW 15

16 ION CHANNELS ARRHYTHMIAS Chien K. Molecular Biology of Cardiovascular disease ION CHANNELOPATHIES CALCIUM CHANNEL Arrhythmogenic right ventricular dysplasia (ARVD 2) Cathecolaminergic polymorphic ventricular tachycardia 16

17 Calcium channelopathies These diseases are due to mutations in the cardiac ryanodine receptor 2 gene leading to an augmentation of cytoplasmatic calcium ion concentration. This provokes higher cellular eccitability and leads to electrical instability. Cathecolaminergic polymorphic ventricular tachycardia Dominant form due to Ryanodine receptor gene mutation Recessive form due to mutations in the cardiac isoform of calsequestrin Adrenergically mediated polymorphic tachycardia Bidirectional ventricular tachycardia 17

18 Cathecolamine (exercise) induced bidirectional VT Calcium channel, acquired form: digitalis intoxication. 18

19 ION CHANNELOPATHIES POTASSIUM CHANNELS, CONGENITAL FORMS Disease GENE CHROMOSOME LQT1 KVLQT1 11p LQT2 HERG 7q LQT3 SCN5A 3p LQT4 ANKYRIN-B 4q LQT5 mink 21q LQT6 MiRP1 21q AFIB KVLQT1 11p Short QT HERG-minK 7q LONG QT SYNDROME Loss of function of potassium channel Syncopal episodes triggered by emotion or stress Seizures Fatal ventricular tachyarrhythmias / sudden death Prolongation of the QT interval in the EKG Romano-Ward» Autosomal dominant Jervell and Lange-Nielsen» Autosomal recessive Acquired Long QT 19

20 Risk stratification in the long QT syndrome. 10% QT>500 High risk >50% Intermediate risk 30-49% QT, gender, mutation QT < 500 ms Short QT syndrome Low risk <30% Priori et al 2003 In 2000 demonstration of short QT associated with malignant ventricular arrythmias Augmented potassium channel function resulting in faster repolarisation with shortening of action potential duration QTc equal or inferior to 300 ms 20

21 Short QT syndrome Short QT syndrome 21

22 The ECG in Brugada syndrome - Prolonged PR - RBBB - ST segment - Negative T waves ECG Drug testing Diagnosis Electrophysiologic study 22

23 Brugada syndrome: type I ECG Brugada syndrome:type II ECG 23

24 Brugada syndrome:type III ECG Incidence 4-12% of unexpected sudden deaths up to 40% of sudden deaths in structurally normal heart most common cause of natural in younger than 50 years in South Asia* *Nademanee et al, Circulation

25 R282H W156X R225W G298S D1595N A735V G1406R R367H 393delF K1500 IN A IR ES IR N1987K T512I H558R G 514C IS S1710L SE M Voltage gradient: the substrate for reentrant arrhythmias 25

26 Effects of sodium channel blockade Long QT3 Basal Unmasking Brugada syndrome by pharmacologic testing. Ajmaline: 1 mg/kg/5 min Flecainide Procainamide: 10 mg/kg/10 min Flecainide: 2 mg/kg/10 min 26

27 Brugada Effects of sodium channel blockade Basal Flecainide Ionic mechanisms are temperature dependent C 36.4 C Link to fever related convulsions and SCN6A 27

28 Brugada syndrome. Logistic regression analysis. Probability of SD after the diagnosis in patients without previous SD Basal abnormal ECG, asymptomatic, non-inducible: 1,8% (0.6-5.) syncope, non-inducible: 4,1% (1.5-12) asymptomatic, inducible: 14,0% (8-23) syncope, inducible: 27,2% (17-40) Drug-induced abnormal ECG, asymptomatic, non-inducible: 0,5% (0.1-3) syncope, non-inducible: 1,2% (0.2-7) asymptomatic, inducible: 4,5% (1-17) syncope, inducible: 9,7% (2-33) Brugada syndrome.logistic regression analysis. Probability of sudden death during life-time (25%) (n=610) Male, Ajmaline-induced ECG, non-inducible: 4,4% Male, basal abnormal ECG, non-inducible: 11,0% Male, Ajmaline-induced ECG, inducible: 23,4% Male, basal abnormal ECG, inducible: 45,1% Female, Ajmaline-induced ECG, non-inducible: 3,0% Female, basal abnormal ECG, non-inducible: 7,6% Female, Ajmaline-induced ECG, inducible: 17,0% Female, basal abnormal ECG, inducible: 35,5% 28

29 Therapy?.if diagnosis is sure.aicd Acute termination of near sudden death: ICD discharge 29

30 Prevention of sudden death: Appropriate ICD shocks Treatment of the acute episode: Near sudden death caused by VF: CPR 30

31 Ventricular arrhythmias during electrocardiographic monitoring DC Shock SCN5A mutations Long QT syndrome: 36 Brugada syndrome: 80 Conduction defect: 12 Long QT-Brugada: 4 Long QT-Cond. Defect: 0 Brugada-Cond. Defect: 3 Atrial standstill: 1 Total

32 GENETIC OVERLAP Conclusions A careful clinical history, physical examination and echocardiogram may help recognize the structural causes of potential sudden cardiac death. The clinical history and the electrocardiogram remain the major tool for the suspicion of inherited arrhythmias. An ECG for everybody at birth and school? 32

33 Our knowledge can only be limited, our ignorance necessarily infinite. Karl Popper 33