Dr Philippe Charron. ESC congress, Stockholm, 29 August 2010

Transcription

1 Inherited cardiomyopathies and and channelopathies: who is at risk for sudden cardiac death? Does genetic profiling predict risk in individual patients? Dr Philippe Charron Centre de Référence pour les Maladies cardiaques héréditaires Département de Cardiologie et Département de Génétique Université Paris VI, Inserm U956, Hôpital Pitié-Salpêtrière, Paris, France ESC congress, Stockholm, 29 August 2010

2 Genetics and Prediction: les liaisons dangereuses? 2010: First complete personal genome sequencing for clinical risk assessment Ashley et al., Lancet 2010 May 1;375:

3 Increasing genetic knowledge Disease HCM DCM ARVC RCM UNCLASSIFIED Genes Sarcomeric protein disease ß-myosin heavy chain Cardiac myosin binding protein C Cardiac troponin I Troponin-T a-tropomyosin Essential myosin light chain Regulatory myosin light chain Cardiac actin a-myosin heavy chain Titin Troponin C Z band Muscle LIM protein Muscle LIM protein Myozenin; Obscurin Glycogen storage disease (e.g. GSD II (Pompe s disease); GSD III (Forbes disease), AMP kinase (WPW, HCM, conduction disease) Danon disease Cytoskeletal genes Dystrophin Desmin Metavinculin Sarcoglycan complex CRYAB Epicardin Nuclear membrane Lamin A/C Emerin Sarcomeric protein mutations (see HCM) Z band ZASP Muscle LIM protein TCAP Myopalladin Intercalated disc protein mutations Plakoglobin Desmoplakin Plakophilin 2 Desmoglein 2 Desmocollin 2 Cardiac ryanodine receptor (RyR2) Transforming growth factor-β3 (TGFβ3) Transmembrane proteins TMEM43 Sarcomeric protein mutations Troponin I (RCM +/- HCM) Essential light chain of myosin ß-myosin; troponin T, cardiac actin Familial Amyloidosis Transthyretin (RCM + neuropathy) Apolipoprotein (RCM + nephropathy) Desminopathy Pseuxanthoma elasticum Haemochromatosis Anderson-Fabry disease Glycogen storage disease Left Ventricular Non- Compaction : G4.5 ZASP a-dystrobrevin Lamin A/C a-actine ß-myosin heavy chain Troponin-T SCN5A Lysosomal storage diseases (e.g. Anderson-Fabry disease, Hurler s syndrome) Disorders of Fatty Acid Metabolism Carnitine deficiency Phosphorylase B kinase deficiency Mildly dilated CM Intercalated disc protein mutations (see ARVC) Mitochondrial cytopathies (e.g. MELAS, MERFF, LHON) Syndromic HCM Noonan s syndrome LEOPARD syndrome Friedreich s ataxia Beckwith-Wiedermann syndrome Swyer s syndrome (pure gonadal dysgenesis) Mitochondrial cytopathy Ionic channel SCN5A RyR2 Muscarinic receptor CHRM2 Other: Familial Amyloid Phospholamban promoter Junctophilin-2 Eur Heart J 2008;29:270-6

4 Concept of phenotypegenotype correlations Large number of possible genes or mutations for a given disease Variable evolution, risk of complications, answer to ttt The precise/right diagnosis could lead to a better risk assessment and specific management

5 (1) Prognosis based on the underlying gene Example in HCM Troponin T cardiac protein C b myosin heavy chain Watkins H et al. NEJM 1995;332:1058 Influence of the gene on the prognosis Phenotype-genotype correlations

6 percent Influence of the gene in HCM Analysis of sarcomeric genes in 197 French families with HCM (Protein C) MYH7 (40%) (bêta myosin) MYBPC3 (42%) Distribution of genes in 197 independent index cases TNNI3 (6%) MYL3 (<1%) MYL2 (4%) TNNT2 (6%) (troponin T) Malignant prognosis P<0.05 TNNT2 MYH7 MYBPC3 Phenotype-genotype correlations Richard, Charron et al. Circulation 2003

7 Influence of the gene in Long QT syndrome Priori et al., N Engl J Med 2003;348:1866 Study of 647 pts from 193 LQT families Cardiac events less frequent in LQT1 pts (30%) than in LQT2 (46%) or LQT3 pts (42%); p<0.01 Genetic locus and QTc are independent predictors of cardiac events. QTc is predictor of risk only in the context of LQT1 or LQT2 loci but not LQT3.

8 Prognostic stratification in DCM (Lamin A/C gene) Natural history of DCM patients (12 LMNA mutations vs 93 pts) Taylor JACC Specific phenotype : - early AV block / sinus dysfunction and/or SV or V arrhythmia - DCM - +/- skeletal myopathy - Specific underlying gene : - Lamin A/C gene mutations - Autosomal dominant inheritance Prophylactic ICD in 19 pts (PM indication) - 42 years; 14 M/ 5 W; LV EF 58%; FU 34 months Appropriate ICD therapy in 42% (8 pts) Meune et al. NEJM 2006;354: Fatkin et al., NEJM 1999;341:1715 Lamin A/C gene mutation specific FU early PM and ICD

9 Prognostic stratification in ARVD/C Study of 135 independent French patients with ARVD/C (PHRC network) Phenotype PKP2 DSP DSG2 DSC2 P value P value (N=40) (N=6) (N=12) (N=2) PKP/DSG/DSP PKP/DSG2 Age at diagnosis 34.0± ± ± NS NS Age at inquest 41.9± ± ± NS NS Gender (M/F) 33/7 0/6 11/1 2/ NS Fam. History ARVD/C 30.0% 33.3% 8.3% 1/2 NS NS Fam. History SD 25.0% 33.3% 8.3% 1/2 NS NS Symptoms 92.5% 100% 100% 2/2 NS NS Sudden death 7.5% 0% 8.3% 1/2 NS NS Syncope / SD 45.0% 50.0% 54.5% 2/2 NS NS Sustained VT 53.8% 50.0% 75.0% 0 NS NS ECG T-wave inversion 87.5% 33.3% 88.9% NS Late potentials % 66.7% 90.0% 2/2 NS NS EP testing + (n=40) 73.1% 50.0% 87.5% 0 NS NS Diffuse RV abn 67.5% 66.7% 58% 1/2 NS NS Low LV EF <45% 10% 33.3% 50% 1/ ICD 47.5% 66.7% 66.7% 0 NS NS PKP: plakophilin DSP: desmoplakin DSG: desmoglein DSC:desmocollin Desmoglein-2 (DSG2) mutations are associated with more frequent LV dysfunction Fressart et al,. Europace 2010; 12(6):861-8.

10 (2) Prognosis based on the underlying mutation HCM related to MYH7 (bêta myosin) mutations Ben Int Mal French population and prognosis in families with 40 mutations in the MYH7 gene % mutations Benign or intermediate or malignant Watkins et al. NEJM 1992;326:1108 Richard et al Circulation 2003;107:2227

11 Influence of the mutation in DCM lamin A/C mutations 27 families 94 mutation carriers 57 months FU Prognosis is related to type of mutations (splice site), and to competitive sport (Cox bivariate analysis) Pasotti et al. JACC 2008;52:1250

12 Influence of the mutation in LQT LQT1 locus -KCNQ1 gene 600 pts with (77) KCNQ1 mutation from 101 families Independent increased risk for cardiac events associated with: Transmembrane vs C- terminus mutations (HR 2.06, p<0.001) Dominant negative versus haplo-insufficiency effects (HR 2.26, p<0.001) Moss et al. Circulation 2007;115:2481

13 Influence of the mutation in Brugada syd SCN5A gene 147 pts with 32 SCN5A mutations Loss of function mutations (leading to premature protein truncation) (T) are associated with more syncope than missense mutations (M), 19/75 vs 2/35, p=0.03 Meregalli et al. Heart Rhythm 2009;6:341

14 (3) Influence of multiple mutations Multiple mutations : Compound heterozygotes (two different mutations within the same gene) Double heterozygotes (two different mutations in two different genes) Homozygotes (the same mutation present on the two alleles of a gene) may explain intra familial variability in HCM : Description of such cases in about 2-5 % of total screened index cases, or 8 to 17% of index cases with a mutation (Richard, Circulation 2003; Begley, Pacing Clin El 2003, Ingles, J Med Genet 2005) Gene dose effect on phenotype

15 Homozygous HCM subjects in Family 733 (Arg869Gly variant in MYH7) Heterozygous - No symptoms 70 y. - Echo : IVS 14 mm EF > 55% - ECG : SR I Heterozygous - Onset/symptoms: 60 y. Atrial fibrillation, Echo: IVS 15 mm, EF > 60% - CHF at 64 y. II Homozygous - 12 y. systolic murmur Echo: 38 mm IVS, EF 80% - 17 y. atrial fibrillation - PM and AVnode ablation at 27 y y.: EF 50%, IVS 20 mm, left atrium 85 mm Homozygous - 8 y. systolic murmur Echo : IVS 15 mm, EF > 60% - 17 y. atrial fibrillation - 20 y. Echo: EF < 50% - PM and AVnode ablation at 28 y. Echo: EF 45%, IVS 17 mm, LA 90 mm Richard et al. JMCC 2000;32:1575

16 Triple mutations in HCM patients Severe phenotype associated with triple sarcomere gene mutations: 4 pts among 488 pts (0.8% of cases) 1 with aborted SD and 3 with risk factors and ICD (2 with appropriate shock) 3 evolved towards end stage HCM (1 HTx and 2 RCT) Girolami, JACC 2010;55:1444

17 Multiple mutations in ARVC/D Experience of the French network : Analysis of all 5 desmosomal genes (PKP2, DSP, DSG2, DSC2, JUP) in all the 135 index cases Multiple causal mutations: in 4% of the 135 independent patients Associated with more frequent sudden death (40% versus 5.3%, p=0.047) and tended to be associated with more frequent LV systolic dysfunction (60% versus 19.3%, p=0.07). Fressart et al,. Europace 2010; 12(6): % 0 % ARVD/C patients sudden death LVEF<45% p=0.047 single multiple p=0.07 single multiple

18 Multiple mutations in ARVC/D Experience of the Padua group (It): Analysis of all 5 desmosomal genes (PKP2, DSP, DSG2, DSC2, JUP) in all the 42 index cases Multiple causal mutations: in 7% (3/42) independent index cases (and additional 7 relatives) Frequent sudden death in multiple mutation carriers (the 3 index cases) and more frequent LV involvement (p=0.025) than single mutation carriers. Bauce et al,. Heart Rhythm 2010; 7:22

19 (4) Influence of modifier genes D I Example: Renin Angiotensin System ACE Gene : chromosome 17q23 intron 16 polymorphism : Insertion 287 pb OR Deletion exon 16 intron 16 exon 17 3 possible genotypes : D/D or I/D or I/I

20 Role of modifier genes in HCM Population: 26 genetic carriers from a single family with a cardiac myosin binding protein C mutation (insg/exon24) Analysis of polymorphisms of 5 genes of the RAAS system (ACE, AGT, AGTR1, C%A, CYP11B2) Study of LV mass/thickness according number of pro-lvh allelles Ortlepp et al. Heart 2002

21 Role of modifier genes in Long QT Genome wide study of QT interval (chip SNPs) in subjects at extreme of QT interval distribution (from 3966 normal subjects) Identification of NOS1AP (nitric oxide 1 adaptor protein) as a modulator of cardiac repolarization (p<10-7 in the total cohort, adjusted) Explain 1.5% of QT interval variability Arking et al. Nature Genet 2006;38:644

22 Role of modifier genes in Long QT Study of nitric oxide 1 adaptor protein (NOS1AP) SNPs in 901 LQT patients NOS1AP polymorphisms are associated: with QTc interval (2 alleles associated with 7 ms or 8 ms prolongation, p<0.05 and p<0.01) with incidence of cardiac events (25.2% vs 18%, p<0.05) Cox analyses: rs is independent prognostic marker in pts with QTc < 500 ms (HR: 1.63, p<0.05) Tomas et al. JACC 2010;55:2745

23 Limitations of available studies regarding phenotype-genotype analyses Some discordances / exceptions Variable evolution among patients with the same mutation/gene Possible methodological biais: Incomplete genetic analyses Retrospective data Small populations No comparative statistical analyses (ex: case record) Inclusion of index cases (probands) only or families with small sample size Genetic heterogeneity: Private mutations (low number of families with the same mutation) Confounding factors contributing to intra familial variability Double mutations Modifier genes Environmental factors

24 A need for key messages and suggestions for clinicians involved in the management of Cardiomyopathies Eur Heart J. 2010, in press

25 Potential situations for genetic testing in CMPs Genetic testing and positive diagnosis ( ) Genetic testing and predictive diagnosis ( ) Genetic testing and prenatal diagnosis ( ) Genetic testing and prognostic testing Genetic testing cannot be systematically recommended for prognostic stratification of a patient with a cardiomyopathy, but should be considered in selected patients or for selected types of cardiomyopathies, in the setting of expert teams after detailed clinical and family assessment. ESC WG Position Statement paper: Eur Heart J, 2010, in press

26 Conclusion Variable phenotype expression of the CMPs and channelopathies age sex causal gene disease causal mutation second mutation physical activity Myocarditis / fever genetic polymorphisms Thank you!