Liens d’intérêt

Congrès-Grants :

Alnylam, Akcea, Prothena, Pfizer, Ionis, Sanofi Aventis, Bayer, Resmed, Novartis, Vifor, DaichiiSankyo.

Cardiac AmyloidosisDiagnostic and Treatment

Journée Néphrologique21/05/2019

Pr Thibaud DAMY

www.reseau-amylose-chu-mondor.org

Consequences of Cardiac Amyloid Infiltration

Stable and Stiff

Interstitial Infiltration

Progressive and Dynamic

Non Immunogenic++++

Associated with Aging-Process

Merlini G, NEJM 2003

↗ Stiffness ↗ Thickness↗ Cellular death

Amyloid fibrils Cardiac Consequences…

↗ Heart Failure↗ Arrhythmias↗ Conduction D↗ Thrombosis

Amyloidosis Classification and Cardiac forms

ACQUIRED HEREDITARY

WT-TTRWild type Transthyretin or

Senile Systemic Amyloidosis

AL

Light Chain

AA

Maladies inflammatoires

mTTR

Hereditary TTR

Fibrinogen

Gelsolin

ApoA1

ApoA2

Lysozyme

Cystatin C

Transthyretin CADefinition and Physiopathology

5

Dissociation

Hereditary : hTTRAutosomal dominant

120 mutations HEART>>>nerve

Senescence or Wild-Type : wtTTR« Cardiac Alzheimer »

¼ of 80yrs old with TTR amyloid deposits in the heart

Conséquences anatomiques et physiopathologiquesde l’infiltration amyloïde myocardique et du SNA

Vasculaire PericardeMyocarde Endocarde

↗ Epaisseur

↗ Rigidité

Dysfonction diastolique

Dysfonction systolique

Thrombose : (EP/AVC)

Mort cellulaire : ↗ Troponine

IT /IM

Rétrécissement

Aortique = 6 à 16%

Ischémie

Nécrose Epanchement

Péricardique

Tamponnade

Cellules “électriques” Système Nerveux Autonome

Trouble du rythme : Arythmie, Flutter

Trouble de la conduction : BAV1-2-3

↘ Fréquence Cardiaque

Insufffisance Chronotrope à l’effort

Hypotension Orthostatique

Présentation cardiologique

Amylose TTR héréditaire Val122Ile homozygote Coeur explanté

Atteinte interstitiellemyocardique

Dyspnée d’effort, IC droiteHFpEF / HVG

Atteinte ValvulaireRAC (bas debit)

Atteinte atrialeFA

Atteinte péricardiqueEpanchement

Atteinte électriqueTbles de conduction

Atteinte SNAI chronotrope

Atteinte vasculaireIschémie, thrombi

Maladie pas si rare...

15% d’amylose dans les HVG avec dysfonction systolique

Rosmini et al., Heart 2017;103:300-306.

5% d’amylose héréditaire dans les bilans d’HVG Damy et al., Eur Heart J 2015 Nov 3.

11% d’amylose chez les sujets noirs consultant pour IC Dungu et al., Circ Heart Fail 2016

21% d’amylose dans l’IC à FE préservée, 29% après 65 ans

13% d’amylose “sénile”Mohammed et al., JACC Heart Fail 2014;2:113-122

González-López et al., Eur Heart J. 2015 Oct 7;36(38):2585-94

Bennani Smires et al., Int J Cardiovasc Imaging 2016;32:1403-1413

16-22% d’amylose dans les RAC serrés traités par TAVI Galat et al. Eur Heart J 2016, Dec 3

Castano A et al. Eur Heart 2017, Oct 7

Consultation cardiologique

71,8%

McCausland et al., Patient 2018

TTR Cardiac AmyloidosisMore frequent thanpreviously thought.

www.reseau-amylose-chu-mondor.org

mTTR-CA: Hereditary TTR-CA

Transthyretin gene (Chromosome

18; 4 exons).

Autosomal Dominant

>100 mutations

Rapezzi C et al, Eur Heart J 2013

3.6% of Africans-Americans!

VAL122ILE

Genetic

sequencing

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 centersPower > 260 patients.Inclusion criteria :

LV wall thickness ≥15mmif familial ≥ 13mm

Exclusion criteria<18 years oldAortic stenosis <1cm²Already known hereditary cardiopathy

TTR genetic testing

Avec le soutien institutionnel

ClinicalTrials.gov Identifier: NCT01623245

AMYLO-STUDY

Senile Systemic Amyloidosis : WT-TTR

Prevalence :

ATTR Deposits in the heart : 25% of subjects older > 80y WT-TTR = « Cardiac Alzeihmer disease »

WT-TTR CA : Prevalence underestimated in Cardiology Setting

Men >Women

Physiopathology unknown : CV Risk factors or Disease?

Diagnosis : TTR-CA with no TTR gene mutation

History Amyloid Infiltration occurs Several Years before CA in

Carpal Tunnel = Syndrome and Surgery.

Lomber Spinal = Stenosis.

Deafness

Gonzales-Lopez et al EHJ 2015

Prevalence of WT-TTR in HFPEF : 13,3%

Castano A, Eur Heart J 2017

•ATTR-CA Senile : 13% HFPEFGonzales et al EHJ 2016

•ATTR-CA hereditary : 8% CMHDamy et al EHJ 2016

No ATTR-CA127

ATTR-CA24

NYHA I, % 6,3% 0,0

NYHA II/III/IV, % 19/64/11 25/75/0

AS : High gradient, % 82 63

Low flow-low gradient REF, %

11 29

Low-flow-low gradient PEF, %

7 8

NTproBNP 1800 3000

Average Mitral Annular S’<6cm/s

AS –TAVI = 16% ATTR-CA

TTR prevalence is clearlyunderestimated

HF-PEF AS+TAVI HCM

Wild-type-TTR 13% 6-16% ?

Hereditary-TTR ? ? 7.6%>65y old

AL ? ? ?

How to diagnose CardiacAmyloidosis?

www.reseau-amylose-chu-mondor.org

The “mimicked” FACE of CA in Cardiology…

Age –Elderly TTR

GenderEthnicity

Black/ Portuguese, Swedish/ Japanese« Non endemic » ethnicity Ando Y, Orphanet journal of Rare Diseases 2013

Rapezzi C et al, Eur Heart J 2013

Cardiac Amyloidosis ?

HCM RCM

Aortic

Stenosis

Hypertensive

CardiopathyHFPEF

With Cardiac Hypertrophy

HFREF With Cardiac Hypertrophy

ExtraCardiacSigns?

DYSPNEA + LVHNo improvement after treatment ; Aggravate on Betablocker

Atrial Fibrillation

Flutter

AVBlock

Pseudo SCA with

No chest pain

Q waveTropo+

History and Symptoms

Cardiac History:

AHF

Flutter, Atrial fibrillation (atrial amyloid deposits)

Atrio Ventricular block, AVB 1, AVB2, AVB3: PM implant?

Extra Cardiac History:

Family…: missing in Elderly patients

Carpal tunnel syndrome / Surgery

Spinal lumbar stenosis

Clinical signs :

Oedema

Jugular distension...

Extracardiac signs : Neurological...Carpal Tunel Sd...

Look like « Normal » HF patient

ECG1,2

• QRS voltage, conduction abnormalities, rhythm disturbances

Echocardiography1–3

• Biventricular hypertrophy, left atrial dysfunction, diastolic dysfunction, longitudinal

dysfunction

Bone scintigraphic imaging

• Diagnostic algorithm proposed based on tracer (e.g., 99mTc-DPD) uptake into myocardial

amyloid and absence of M-protein4

CMRI1–3

• Atrial and ventricular amyloid infiltration, LGE, T1 mapping, ECV

Serum cardiac biomarkers1,3

• NT-proBNP, troponins

Extra Cardiac and Cardiac biopsy1

• For definitive confirmation of amyloid deposition

ECV, extracellular volume

1. Ruberg & Berk Circulation 2012;126:1286–300; 2. Dharmarajan et al. J Am Geriatr Soc 2012;60:765–74; 3. Gertz et al. J Am Coll Cardiol 2015;66:2451–66;

4. Gillmore et al. Circulation 2016;133:2404–12

Clinical Tools for Diagnosis and Assessment of Cardiac Symptoms

Echographie trans-thoracique

• Cardiopathie hypertrophique biventriculaire (12mm)• Homogène ou asymétrique• +/- Valves, Septum inter-auriculaire

• Aspect brillant / granité du myocarde

• FEVG préservée jusqu’au stade tardif

• Ventricule de taille normale / réduite

• Dilatation bi-auriculaire

• Epanchement péricardique de faible abondance

• Profil mitral pseudo-normal ou tb relaxation

restrictif à un stade avancé

• Diminution des vitesses TDI

• Altération du Strain global longitudinal avec épargne

apicale jusqu’au stade tardifPhelan et al., Heart 2012 Oct;98(19):1442-8

Phénotype obstructif

Echographie trans-thoracique

Stade « dépassé »

SGL-2%Non hypertrophié

Non restrictif

Cardiac scintigraphy with Bone Tracer

Galat A, Amyloid 2015, in press

Usefulness of 99mT HMDP/DPD/PYP scintigraphy in the aetiological diagnosis and prognosis of cardiac amyloidosis

AL

HR

/SR

rati

o

m-TTR wt-TTROther

cardiopathy

0

2,00

4,00

6,00

P = 0.003

P = 0.024

log-Rank test: 5.04; p=0,025

Time (days)

MA

CE

-fre

e

surv

ival

HR/SR <1,94

HR/SR ≥1,94

0 100 200 300 400 500

0

0,2

0,4

0,6

0,8

1,0

5 minutes 3 heures

Heart Retention

Whole Body Retention

HR / WBR ratio

International Statement

Gillmore J et al, Circulation 2016

STRONG cardiac fixation = TTR-CA (wild-type or hereditary)NO cardiac fixation = you can’t exclude AL

7% if >80yold

DANGER:treat TTR-CA with gammopathyWITHCHEMO

Interpretation of Bone Scintigraphy in case of CA suspicion

Rapezzi C et al, Eur Heart J 2013RA. Kyle et al New Engl J Med 2006

No Gammopathy*

+

Cardiac fixation

CA-TTR Amyloidosis

Genetic Testing

Senile

TTR-CA

Hereditary

TTR-CA

Gammopathy*

+

No or Cardiac fixation

CA-AL Amyloidosis?

BIOPSY

No Gammopathy*

+

No Cardiac fixation

CA?

Cardiac MRI

Biopsy?

*Gammopathy work-up : -EPP, Immunofixation, light chain dosage, -Bence Jones proteinuriaGillmore J et al, Circulation 2016

7.7% of AL-CA have Cardiac Fixation

MADI Score and AL-CA

MADI OrganFixation

Prevalence in AL

0 No 60% (n=39)

1 ExtraCardiac 32% (n=21)

2 Cardiac Fixation 4.6% (n=3)

3 Cardiac and ExtraCardiac

3.1%(n=2)

7.7% of AL-CA have cardiac fixation.AL-CA patients have a worse prognosis

Malka N, 6ème, JFMA Manuscript in preparation

Genetic testing : TTR FACIdentification of the TTR Mutation

Intron1 Intron2 Intron3

1 2 3 45’ 3’

Nucleotide substituion

AAT GTG GCC GTG CAT GTG TTCVal30

AAT GTG GCC ATG CAT GTG TTCMet30

TTR amyloidosis diagnosis

Rapezzi C et al, Eur Heart J 2013

CARDIAC SYMPTOMS

TTR Cardiac Amyloidosis

Prevalence of Gammopathy

RA. Kyle et al New Engl J Med 2006

Biopsy needed ? Amyloidosis Diagnosis = Amyloid Deposits

1. Uncertained Diagnosis2. Mandatory if Gammopathy

Extra-cardiac(Salivary Gland)

Cardiac

New Management and Treatment in Cardiomyopathies

Cardiac Amyloidosis

www.reseau-amylose-chu-mondor.org

Cardiac amyloidosis and Guidelines

Do not apply ESC HF Guidelines

•Cardiac Infiltration

•Continuous process

•Restriction/Celluler Death

Patient – Specific Biomechanical Modeling of Cardiac Amyloidosis, A case StudyD. Chapelle, A. Felder, R; Chabiniok, A. Guellich, J-F Deux and T. Damy

Chapelle et al FIMH 2015

92bpm

63bpm

HR↘=↘CO

CardiacOutput = HeartRate x SV

Cardiac Treatment of CA = CHADS-TOP!

C: Prevent conduction disorders/rhythm : PM/ ICD / CRT?

H: Maintenance of HIGH HEART RATE…even if PM needed

A: Prevent cardiac embolism (PE/Stroke…) : ANTICOAGULATION

D: DIURETIC : adapt the dose to volemia.

S-TOP: betablocker, ivabradine, calcium blocker…(+/-ACE).Digoxin: dangerous?

CHADS-TOPConductionHigh Heart RateAnticoagulationDiureticS-TOP BB….

Cardiac Amyloidosis Specific TTR Treatments:

Stop the infiltration process!

www.reseau-amylose-chu-mondor.org

TTR Therapeutic approaches

Antisens oligonucleotides and siRNAs

Drugs Ionis Patisiran Revusiran

Trial Phase 3 NeuroTTR Phase 3Appolo

Endeavour

AmyloidoisosisType

Hereditary TTRNeuro>>Cardio(Data on Senile)

Hereditary TTRNeuro>>Cardio

Hereditary TTRCardio

Administration Subcutaneous Intravenous Subcutaneouss

Cardiac Effect IVST NTproBNP-IVSTSystolic function

↘ or→

STOP

Where we are? ATU Neuro TTR ATU Neuro TTR

TTR Therapeutic approaches

ATTR-ACT: Transthyretin Amyloid Cardiomyopathy Tafamidis Study.

Multicenter, international, phase 3, double-blind, placebo-controlled, randomized trial

441 patients with ATTR-CM were randomized in a 2:1:2 ratio to receive tafamidis 80 mg, 20 mg or placebo for 30 months.

Maurer M et al, NEJM 2018

Tafamidis reduces all-cause mortality and cardiovascular-related hospitalizations over 30 months

Maurer M, NEJM 2018

Tafamidis Reduces All-Cause Mortality of 30%

Tafamidis (78/264, 29.5%) vs. Placebo (76/177, 42.9%)

Mortality hazard ratio = 0.70; 95%CI (0.51-0.96), P=0.0259

Maurer M, NEJM 2018

Tafamidis reduces the decline in the 6MWT distance and KCCQ-OS score at 30 months

Maurer M, NEJM 2018

Number of patients Needed to Treat with Tafamidis

ATTR-ACT (Tafamidis)

NNT for all-cause mortality = 7.5 at 30 months

PARADIGM (Entresto, LCZ696):

NNT for all-cause mortality = 35.7 at 42 months

(Note that NNT should be even higher at 30 months)

Maurer M, NEJM 2018

Conclusion : TTR amyloidosis

Underestimated and poor prognosis

Precision medicine = Right Diagnosis = Right Management

Two types of TTR : Senile >> Hereditary : genetic testing.

Rule out AL amyloidosis : Emergency

Need to adapt cardiac management…

New specific treatment : Tafamidis!

We can now change patients outcome…

www.reseau-amylose-chu-mondor.org

Medicine

Cardiology: T Damy, S Guendouz, N Lellouche,

L Hittinger, JL Dubois-Randé, N Elbaz, D Bodez,

A Galat, S Rouffiac, G Abeshira, S Oghina, P

Issaurat, V Ouazana

Neurology: V Planté-Bordeneuve, S Hayet

Psychology: J Pompougnac

Neuro-muscular disease: J Authier, G Bassez

Nephrology: V Audard, P Rémy, K El Karoui

Haematology: C Haioun, K Belhadj, J Dupuis, F

Le Bras, Louise Rollin

Internal medicin: M Michel

Hepatology: C Duvoux

Dermatology L Allanore

Genetic: B Funalot

Surgery

Cardiac surgery: T Folliguet, JP Couetil, E

Bergoend,

C Radu, M Hillion

Hepatic surgery : D Azoulay

Orthopedy : A Pidet

Platforms

Haematology : O Wagner-Ballon

Electrophysiology : JP Lefaucheur

Pathology : A Moktefi, E Poullot

Sequencing : B Funalot, P Fanen, B

Hebrard, C Mekki

Immuno-biology: V Frenkel

Radiology: JF Deux

Scintigraphy : E Itti, M Abelisi

Clinical research

Cardiology : M Kharoubi

Administration

Coordination : C Henrion

Secretariat : I Vallat