Transthyretin cardiac amyloidosis, not so rare.

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RESEAU AMYLOSE CHU MONDOR Transthyretin cardiac amyloidosis, not so rare. www.reseau- amylose-chu-mondor.fr IMRB, U955 AMYLOIDOSIS MONDOR NETWORK Pr Thibaud DAMY Unité insuffisance cardiaque et transplantation Service de cardiologie CHU Mondor A-TVB A-TVB

Transcript of Transthyretin cardiac amyloidosis, not so rare.

Page 1: Transthyretin cardiac amyloidosis, not so rare.

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Transthyretin cardiac amyloidosis,

not so rare.

www.reseau- amylose-chu-mondor.fr

IMRB, U955

AMYLOIDOSIS MONDOR NETWORK

Pr Thibaud DAMY

Unité insuffisance cardiaque et transplantation

Service de cardiologie

CHU Mondor

A-TVBA-TVB

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Conflict of interest

• PFIZER

• ALNYLAM

• ISIS

• GSK

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Amylose : Définition

Dépôts de SA Extracellulaire Homogène, éosinophile Marqués au rouge congo Protéines fibrillaires attachées

entre elle par le Serum Amyloid P component

~20 Précurseurs protéiques connus riches en feuillets

Anomalies de structure secondaire

↓↓solubilité

Merlini, NEJM 2003

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P Elliot, Eur Heart J, 2008

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Genetic and sarcomeric etiology

(Myosin binding protein C)

(Beta myosin heavy chain)

(Troponin T)

HCM: Aetiological heterogeneity

Guidelines CMH EHJ 2014

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Classification des amyloses

ACQUISES HEREDITAIRES

AL

AA

SENILE : WT-TTR •Transthyrétine mutée : mTTR

•Fibrinogène

•Gelsoline

•ApoA1

•ApoA2

•Lysozyme

•Cystatin C…

•Transthyrétine sauvage

•Maladies inflammatoires

•Chaînes légères

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Transthyrétine (TTR)

• Sites de synthèse

– Foie (95%), plexus choroïdes, rétine

• Tétramère (55 kDa)

– Transporte thyroxine et rétinol (RBP)

Bulawa et al PNAS, 2012

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Amylose TTR héréditaire (FAP)

• Gène de la transthyrétine (Chromosome 18; 4 exons).

• Autosomique dominant

• Séquençage génétique

• >100 mutations

Rapezzi C et al, Eur Heart J 2013

3,9% African-americans carry the ATTR Val122ile

0,038% homozygotes

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Damy et al EHJ 2015

298 patients

74%men

Caucasian origin: 76%

African (black) origins : 23%

Carpal tunnel : 6%

Neuropathy : 8%

Family history of HCM: 19%

Hypertension : 50%

Atrial fibrillation: 34%

NYHA III to IV: 36%

LVEF<30%: %

NTproBNP: 2546(857-5341)

Objective : Frequency of TTR mutation in HCM

patients>10 centers

Power > 260 patients.

Inclusion criteria :

LV wall thickness ≥15mm

if familial ≥ 13mm

Exclusion criteria

<18 years old

Aortic stenosis <1cm²

Already known hereditary cardiopathy

TTR genetic testingAvec le soutien

institutionnel

ClinicalTrials.gov Identifier: NCT01623245

AMYLO TTR STUDY

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Damy et al EHJ 2015

17 with ATTR mutation 15 with ATTR mutation and CARDIAC AMYLOIDOSIS

Prevalence of ATTR+CA in HCM = 5,0%

ClinicalTrials.gov Identifier: NCT01623245

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R Frequency of mTTR-CA depending on class of age and origin

noTTR,caucasian

no TTR afro origin

TTR caucasian

TTRafro origin

23%

33%

6,1%4,3%

2,4%

Prevalence of ATTR+CA in HCM with ≥ 55years old = 7,6%

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R Factors associated with Cardiac Amyloidosis vs other HCM in the

AmyloTTRstudy

Damy et al EHJ 2015ClinicalTrials.gov Identifier: NCT01623245

• AFRICAN origins

• Carpal tunnel syndrome

• ECG Low voltage

• Neuropathy

• LGE et the MRI

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Amylose systémique sénile

• Transthyrétine non mutée

• 25% >85 ans (séries autopsiques)

• Homme âgé (98%) :

• Fréquence sous estimée+++

• Source : Transthyrétine sauvage (foie)

• Organe : Cœur, Canal carpien, canal lombaire…

• Diagnostic difficile à affirmer en l’absence de preuve

histologique (biopsie myocardique : problème éthique).

•Intérêt de la scintigraphie technétium DPD/ HMDP+++

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• Autopsy LV specimens : 109 HFPEF without known Amyloidosis; 131 control subjects.

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Gonzales-Lopez et al EHJ 2015

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Prevalence of WT-TTR in HFPEF

13,3%

Gonzales-Lopez et al EHJ 2015

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TTR amyloidosis and aortic stenosis

• Objective: pathological findings following TAVI

• 20 patients with TAVI

• Valve explanted at autopsy (n=17) or surgery( n=33)

Nietlispach et al J Am Coll Cardiol Intv 2012

• 33% of Cardiac amyloidosis

• Likely played a role in poor outcome in 3 patients

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R Aortic stenosis and transthyretin cardiac amyloidosis:

the chicken or the egg?A Galat, A Guellich, D Bodez, M Slama, M Dijos, D Messika Zeitoun, O Milleron, D Attias, JL

Dubois-Randé, D Mohty, E Audureau, E Teiger, J Rosso, JL Monin, T Damy

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%100%

Senile systemic amyloidosis

Amyloid deposits when cardiac biopsy

Strong heart retention at bone scintigraphy

Diffuse late gadolinium enhancement

LVEF ≥50

Low-flow low-gradient

Stroke volume index <35ml/m²

Mean transvalvular gradient

Atrial fibrillation

NYHA III-IV

Aims : report cases of patients with both TTR-CA and AS in order to describe

their specific phenotype, management and outcomes.

Six cardiologic French centers identified retrospectively cases of patients

with severe or moderate AS associated with TTR-CA hospitalized during the

last six years

•Valve replacement was surgical

in 63% and via transcatheter in

13%.

•Median follow-up in survivors

was 33 (16;65) months.

•Mortality was of 44% (n=7).

Galat A, POSTER JESFC and European Heart Journal 2016, in press

Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pattern and

carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management

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Prevalence of TTR amyloidosis in Cardiac amyloidosis : ?

A

C

A’ B’

C’

B

D E

Galat A, European Heart Journal 2016, in press

AMYLO-CARTESIANPrevalence and Post-surgical Outcomes

of CARdiac Wild-type TransthyrEtin

amyloidoSIs in Elderly Patients With

Aortic steNosis Referred for Valvular

Replacement. (AMYLOCARTESIAN)

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Amylose TTR héréditairesNouvelles stratégies thérapeutiques

Neurodegeneration

Stabilisateurs du

tétramère:

- Fx1006A

- Diflunisal

Réduire l’expression

du précursseur:

therapie génique

(ASO, siRNA)

« Résorption de SA

Par dépletion de la

SAP: CPHPC

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Conclusion 1

• Transthyretin amyloidosis had a bad prognosis

• TTR-CA needs specific cardiologic treatment to prevent HF,

AV block and thrombosis.

• Clinical trial on TTR Therapies are undergoing

• TTR-CA prevalence was clearly underestimated.

• Increase cardiologist awareness is needed

• Diagnosis of TTR-CA may improve outcome

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All the patients with HCM, AS, HF-PEF are not amyloidosis!

But many are…

Conclusion 2…

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Vendredi 3 juin 2016, 4ème journéemultidisciplinaire de l’amylose

• Un grand merci à tous les investigateurs

Amylose : Du diagnostic au traitement

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Plus d’informations…

Tel : 0149812253

[email protected]

www.reseau- amylose-chu-mondor.fr

• Pour les patients

• Pour les médecins : vidéos, triptyque…

Triptyque - Amylose Cardiaque – Réseau Amylose Mondor

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R Réseau Amylose - CHU H Mondor

IMRB, U955

Cardiologie : T Damy, CM Tissot S Guendouz, A Galat, J Ternacle, N LelloucheNeurologie : Pr V Planté-BordeneuveNéphrologie : P Rémy, V AudardHématologie : Pr C Haioun, J Dupuis, K BelhadjMedecine Interne : M MichelHépatologie : Pr C Duvoux

Greffe hépatique : Pr D AzoulayGreffe cardiaque : Pr JP Couetil, Dr E Bergoend, Dr C Radu,Dr M Hillion

Imagerie Cardiaque : JF Deux, Pr A Rahmouni, J MayerMédecine Nucléaire : J RossoNeurophysiologie : JP LefaucheurAnatomie-pathologie : Nicole BenhaiemGénétique : Pr. B Funalot, B Coste, P FannenImmunologie : V Frenkel

Recherche: 4 Ingénieurs• S Rappeneau, • A Guellich, • M Kharoubi• F Gorram