Dilated cardiomyopathies. Gene mutations and beyond.

Transcription

1 Dilated cardiomyopathies. Gene mutations and beyond. Stephane Heymans Dep. of Cardiology, CARIM, Maastricht University Medical Centre, Ward Heggermont Job Verdonschot Mark Hazebroek George Summer Hanspeter Brunner-Larocca Jort Merken Kasper Derks Paolo Carai W.Verhesen B. Schroen R. Van Leeuwen

2 Pathogenesis dilated cardiomyopathies Viral Immunemediated Genetic / familial Toxic Rhythm

3 Gene-environmental interactions in dilated cardiomyopathies Lamin A/C Titin Doxorubicin Pregnancy Gene mutations & epigenetics Acquired diseases (treat!) (hypertension, diab, chemotherapy, viruses, immune, arrhythmias) Non-ischemic, dilated, cardiomyopathy

4 Cardiomyopathies: Maastricht multidisciplinary clinical care program Deep phenotyping! History taking. Blood. Imaging. Biopsies! Genetics!

5 Cardiac biopsies (pathology/virology) Inflammation: CD3, 4, 8, 45, -68/mm 2 Viruses: PVB19, HHV4, HHV6, EV, Borr. Storage diseases Cardiotoxicity

6 Cardiomyopathies: genetics Cardiogenetics (in 76 % of patients) 47 genes panel (including titin) Over 30 % gene mutations Sarcomeric Nuclear envelop Mytochondrial Dystrophin-sarcoglycan Cell membrane

7 Equally high diagnostic yield of genetic testing in hypokinetic non-dilated CMP >< DCM HNDC (n=262) Dilated CMP (n=127) Hypokinetic non-dilated Familial inheritance (36%) Familial inheritance (31%) No familial background No familial background Hazebroek M. et al. Circ Heart Fail Mar;11(3):e004682

8 Equally high diagnostic yield of genetic testing in hypokinetic non-dilated CMP >< DCM HNDC DCM Mutation (35 % of familial) Mutation (29% of familial) No familial background No familial background Hazebroek M. et al. Circ Heart Fail Mar;11(3):e004682

9 Diagnostic yield of genetic testing equally high in familial vs. non-familial CMPs HNDC DCM Mutation in 13 % of non-familial Mutation in 18% of non-familial) No Genetic/familial No Genetic/familial Hazebroek M. et al. Circ Heart Fail Mar;11(3):e004682

10 Worse prognosis in familial genetic/familial forms both in DCM and in HNDC Dilated cardiomyopathy (n=262) Hazebroek M. et al. Circ Heart Fail Mar;11(3):e004682

11 Worse prognosis in familial genetic/familial forms both in DCM and in HNDC Hypokinetic non-dilated CMP (n=127) Hazebroek M. et al. Circ Heart Fail Mar;11(3):e004682

12 Genotype phenotype Gene mutation carriers only 50 % CMP DCM: up to 40 %. Major gap! Acquired diseases! Epigenetic factors. microrna & lncrnas DNA modifications

13 Cardiomyopathies: interplay of (epi)genetic and environmental factors Preclinical stage Cardiomyopathy Ageing & hormonal factors; puberty and pregnancy! Epigenetic factors/modifiers Gene mutation Prognosis & severity! Dilated/hypertrophic/ arrhythmogenic. Acquired/environmental factors

14 Interaction between gene mutations and acquired diseases predict DCM outcome Hazebroek M. et al. JACC, 2015;

15 Pathogenesis non-ischemic/dilated cardiomyopathies Viral Immunemediated Gene mutations Toxic Rhythm

16 Cardiomyopathies: interplay of genes and environmental factors Preclinical stage Cardiomyopathy Ageing & hormonal factors; puberty and pregnancy! Epigenetic factors/modifiers Gene mutation Prognosis & severity! Dilated/hypertrophic/ arrhythmogenic. Acquired/environmental factors

17 Treatment of inflammatory cardiomyopathy

18 Immunosupression results in a better outcome

19 Increased Prevalence of Truncating Variants in Peripartum CMP similar to idiopathic dilated CMP Prevalence: 15 % of pathogenic gene mutations in peripartum CMP >< 0-1 % in normal population Ware JS et al. N Engl J Med 2016;374:

20 Pathogenesis non-ischemic/dilated cardiomyopathies Viral Immunemediated Genetic / familial Toxic Rhythm

21 Patient, female, 34 years old Becker disease: dystrophin gene mutation Normal cardiac function 3 months before Flue like symptoms, followed by severe dyspnoe Echocardiography: Severe cardiac dysfunction (EF 15 %) Cardiac dilatation (EDD 68 mm) Cardiac biopsies: Epstein Barr virus (820 copies/µg DNA)

22 Link between hereditary and viral cardiomyopathies Viral protease cleaves dystrophin disruption of the dystrophin glycoprotein complex similar to hereditary abnormalities in dystrophin expression

23 Patient, male, 34 years old Cardiac biopsies: EBV + inflammation CD45b (T-lymphocytes) Dystrophin-1 Dystrophin-2 Dystrophin-3

24 Viral cardiac infection and genetic predisposition DCM Dystrophin abnormality Severe cardiac dilatation and failure Viral infection in the heart

25 How does a virus myocarditis and dysfunction? Immunogenetic susceptibility Cardiac failure Environmental factors Disease/stress/fatigue Hyperinflammation Additional viruses: EBV HHV6

26 Pathogenesis non-ischemic/dilated cardiomyopathies Viral Immunemediated Genetic / familial Toxic Rhythm

27 Immunogenetic susceptibility? One out of thousand.

28 Enrichment of monogenetic CMPmutations in myocarditis patients Enrichment of: BAG3, DSP, PKP2, RYR2, SCN5A, TNNI3 Belkaya S., JACC 2017, 69: p

29 Cardiomyopathies: interplay of genes and environmental factors Preclinical stage Cardiomyopathy Ageing & hormonal factors; puberty and pregnancy! Epigenetic factors/modifiers Gene mutation Prognosis & severity! Dilated/hypertrophic/ arrhythmogenic. Acquired/environmental factors

30 MicroRNAs in arrays of CVB3-induced viral myocarditis in mice and humans Inflammation Susceptibility Costen MF, et al. Circulation Research Aug 3;111(4):

31 Epigenetic immune-background: micrornas modulate myocarditis Hyper-inflammation Virus replication mir-21 mir-155 mir-146b mir-590 mir-221 mir-222? mir-221 (CVB3) mir-222 (CVB3) Zao S. et al; Cardiology Aug 13;132(3): Zhang Y, et al; Sci Rep Mar 2;6:22613 Heggermont W, et al; Eur Heart J Nov 7;36(42):2909 Corsten M, et al. Circ Res. 2012; 128(13):

32 LNA-anti-155 LNA control Human VM Mouse VM Carai P. Inhibition of mirna-155 prevents cardiac injury in viral myocarditis Human: mir-155 in situ hybridsation: Macrophages and T-cells Mouse: mir-155 in situ hybridsation Macrophages and T-cells necrotic LV area (%) LNA control LNA-antimiR-155 sham * VM Corsten M, et al. Circ Res. 2012; 128(13):

33 Epigenetic immune-background: micrornas modulate myocarditis Hyper-inflammation Virus replication mir-21 mir-155 mir-146b mir-590 mir-221 mir-222? mir-221 (CVB3) mir-222 (CVB3) Heggermont W, et al; Eur Heart J Nov 7;36(42):2909 Zhang Y, et al; Sci Rep Mar 2;6:22613 Zao S. et al; Cardiology Aug 13;132(3): Heymans S. et al. JACC, 2016; p

34 Ward Heggermont Inhibition of mir-221/-222 in vivo aggravates cardiac inflammation scrambled control + VM antagomir VM Heggermont et al. Eur. Heart J. 2015; 36(42):

35 MiR-221/222 inhibition increase of interferon regulatory factor-2 (IRF2) CVB3 replication IRF2 is a target of mir-221/222 luciferase signal (Fluc/Rluc) IRF2 3 UTR *** ** pre-nc pre pre-29b IRF2 3 UTR x pre-nc pre pre-29b mir-221/222 inhibition in vivo increases viral load CVB3/GAPDH VM day 7 VM day 4 CVB CVB3/GAPDH antagomir control antagomir CVB3 ** Heggermont et al. Eur. Heart J. 2015; 36(42):

36 Implications. Phenotype and prognostic relevance of gene mutations depend on: Presence of other acquired diseases! Acquired (toxic, arrhythmogenic, viral or inflammatory CMPs) also pending on genetics: Look for gene mutations! Predict response to therapy? Pinto YM et all. Eur Heart J :1850-8

37 Left ventricular reversed remodeling in DCM (treatability) genetics Verdonschot J. et al. Submitted.

38 Left ventricular reversed remodeling in DCM (treatability) genetics Decreased treatability with lamin A/C, RBM20, PLN gene mutations Improved treatability if no or titin-gene mutation

39 But: titin (TTNtv) mutated patients have more arrhythmias!! Well treatable: increased reversed remodelling! Life threatening arrhythmias at long term! Mainly in those patients with additional environmental factor! Biopsies:histology & RNA-sequencing Fibrosis increased Mitochondrial energetics strongly altered Plasma/serum Metabolic alterations

40 Genetics with 47 genes core panel Maastricht cohort Corepanel + TTN Cardiomyopathy N=302 Job Verdonschot Group 1: TTNtv + N=36 Group 2: Other mutations N=40 Group 3: No mutations N=226 Prevalence TTNtv: 11,9% Prevalence: 13,2% Verdonschot J., et all, in revision.

41 Increased life-threatening arrhythmias in TTNtv patients Verdonschot J., et all, in revision.

42 Arrhythmias mainly in those with additional environmental trigger Genetic only Viral, inflammatory, toxic, tachy Verdonschot J., et all, in revision.

43 Increased fibrosis in TTNtv DCM in cardiac biopsies 30 Interstitial fibrosis in EMB p=0.002 p= p= CFV (%) TTNtv Other No mutation Verdonschot J., et all, in revision.

44 But decreased cardiac mass in TTNtv patients

45 Mitochondrial energetics strongly altered (RNA seq & KEGG pathway) Verdonschot J., et all, in revision.

46 Conclusion 1: DCM interplay between (epi)genetics and environmental factors. Viral Gene mutations Immunemediated Toxic Rhythm

47 Future perspectives Look for acquired diseases and other etiologies even if a gene mutations is found! Detailed history! Blood & cardiac biopsies! Look for gene mutations in acquired CMPs! Toxic CMPs: gene mutations? Peripartum CMP: gene mutations = DCM!* Takotsubo CMP Viral CMP Inflammatory or autoimmune CMP Tachy CMP *Ware JS et all. N Engl J Med Jan :233-41

48 Conclusion 2: non-coding micrornas: epigenetic regulators of myocarditis Hyper-inflammation Virus replication mir-21 mir-155 mir-146b mir-590 mir-221 mir-222? mir-221 (CVB3) mir-222 (CVB3) Heggermont W, et al; Eur Heart J Nov 7;36(42):2909 Zhang Y, et al; Sci Rep Mar 2;6:22613 Zao S. et al; Cardiology Aug 13;132(3): Heymans S. et al. JACC, 2016; p

49 Conclusion 3: genetics help to predict treatability in DCM patients Fibrosis & arrhythmias Fibrosis & arrhythmias Decreased treatability with lamin A/C, RBM20, PLN gene mutations Improved treatability if no or titin-gene mutation (but more fibrosis and arrhythmias)

50 University Hospital Maastricht, Dep. of Cardiology, HP. Brunner-Larocca H. Crijns C. Knackstedt N. Lencer V. van Empel P. van Paassen A. Papageorgiou B. Schroen M. van Bilzen R. Dennert M. Hazebroek J. Merken J. Verdonschot Acknowledgements Cardiogenetics, Maastricht - H. Brunner - I. Krapels - E. Vanhoutte - A. van den Wijngaard R. Van Leeuwen W. Verhesen MEDIA Eu-Mascara Homage, Fibrotargets CardiomiR

51 Current genetic guidelines Genetic testing merely in specific cardiomyopathies HCM RCM LVNC DCM ARVC HNDC?

52 Equally high diagnostic yield of genetic testing in hypokinetic non-dilated CMP >< DCM HNDC (n=262) Dilated CMP (n=127) Hypokinetic non-dilated Familial inheritance (36%) Familial inheritance (31%) No familial background No familial background

53 Equally high diagnostic yield of genetic testing in hypokinetic non-dilated CMP >< DCM HNDC DCM Mutation (35 % of familial) Mutation (29% of famili No familial background No familial background

54 Diagnostic yield of genetic testing equally high in familial vs. non-familial CMPs HNDC DCM Mutation (13 % of non-familial) Mutation (18% of non-familial) No Genetic/familial No Genetic/familial

55 Diagnostic yield of genetic testing equally high in familial vs. non-familial CMPs HNDC (n=262) Dilated CMP (n=127) Hypokinetic non-dilated Familial inheritance (36%) Familial inheritance (31%) Mutation (20%) Mutation (18%) No Genetic/familial No Genetic/familial

56 Worse prognosis in familial genetic/familial forms both in DCM and in HNDC Dilated cardiomyopathy (n=262)

57 Worse prognosis in familial genetic/familial forms both in DCM and in HNDC Hypokinetic non-dilated CMP (n=127)