Amiloidosi: dalla fisiopatologiaalle nuove terapie

Marco CanepaUniversità degli Studi di Genova

IRCCS Policlinico San Martino, Genova

Ambulatorio Scompenso Cardiaco/

Cardiomiopatia Ipertrofica

marco.canepa@unige.it

Donnelly et al. Cleve Clin J Med 2017

AL ATTR

months years

P

R

O

G

N

O

S

I

S

P

R

O

G

N

O

S

I

S

IMMUNOGLOBULIN

LIGHT CHAINSTRANSTHYRETIN

Grogan et al. Heart 2017

Amyloid Light-Chain (AL)

Heart failure, bradyarrhitmias, LV hypertrophy associated with

orthostatic hypotension or syncope, peripheral or autonomic neuropathy,

carpal tunnel syndrome, weight loss, fatigue, hepatomegaly or nephrotic syndrome

ECG and echocardiogram (or MRI); NTproBNP and troponin;

cardiologic counseling→ suspect of CARDIAC AMYLOIDOSIS

Serum/urin protein electrophoresis and immunofixation;

quantification of serum free light chains k/L

Bone marrow and fat aspirate

with Congo red staining

Bone scintygraphy

with 99Tc-DPD/HMDP/PYP

ATTR-CA

unlikely

ATTR-CA

likely

Imunoisto & mass

spectr

AL-CA

likely

AL-CA

unlikely

TTR

genotyping

Organ biopsy if high

suspicion

ATTR

wt

ATTR

m

Organ biopsy if high

suspicion

Modified from Maurer et al. Jour Card Fail 2016

CLINIC SUSPICION

CARDIAC TESTING

AL EXCLUSION

ATTR-CM: an evolving disease

❖Difficult diagnosis, biopsy needed

➢Non-invasive diagnosis possible

Until few years ago … Since 2018 …

0 <

>=

Bone scintygraphy with 99Tc-DPD/HMDP/PYP

Gillmore et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis CIRC 2016

RETINOL

RETINOL

BINDING

PROTEIN

THYROXINE

(T4)

T4

BINDING

POCKET

Amyloid Tranthyretin (ATTR)

TTR TETRAMERS

(soluble) MONOMERSFIBRILS

(insoluble)

AGING ATTR-wt

(wild-type, senile)

ATTR-m

(mutation)

MUTATION

ATTR-CM

<30%

>70%

ATTR-m vs. ATTR-wt in real world

Canepa et al. ATTR-ACT vs. real world. EJHF 2019

ATTR-m vs. ATTR-wt in real world

¿ CLINICAL SUSPICION ?

Papoutsidakis et al. Jour Card Fail 2018

Diagnostic delay in a ATTRwt-CM patient

Maurer, Rapezzi et al. CIRC 2017

Witteless et al. JACC HF 2019

MEDICALINTERVIEW

Symptoms of

polyneuropathy

and/or

dysautonomia

Spontaneous

rupture of the

distal biceps

tendon

Bilateral

carpal tunnel

syndrome

Lumbar

spinal

stenosis

Papoutsidakis et al. Jour Card Fail 2018

5-10 years – 40-50% of pts 6-12 months - 95% of pts

Diagnostic delay in a ATTRwt-CM patient

Modified from Sperry et al. JACC 2018

TTR Amyloid Fibrils Left ventricular

hypertrophy

Selezione da archivio informatico di pazienti

maschi sottoposti a chirurgia per tunnel carpale bilaterale

negli ultimi 10 anni; conferma dello stato vitale

con sistema informatico

Contatto telefonico per 1)spiegazione preliminare dello

studio, 2) valutazione preliminare dei criteri dei inclusione, 3) acquisizione preliminare del consenso

informato

Visita presso ambulatorio, con esecuzione di ECG,

ecocardiogramma, prelievo ematochimici

Prosecuzione dell'iter diagnostico/terapeutico per

sospetta cardiomiopatia infiltrativa amiloidotica

secondo le indicazioni delle linee guida internazionali

SCREENING DELL’AMILOIDOSI CARDIACA

DA DEPOSIZIONE DI TRANSTIRETINA

IN PAZIENTI OPERATI PER

SINDROME DEL TUNNEL CARPALE BILATERALE

(STUDIO ACTUAL)

Stimati

100 pazienti

Stimati

80 pazienti

Stimati

60 pazienti

Stimati

10 pazienti

Autorizzato dal CER in data 7/10/2019 e

con delibera n. 1730 del 6/11/2019 del DG

ECG

HCM: Marian and Braunwald, Circ Res, 2017Amyloid: Falk, JACC; 2016

HCM

CARDIAC

AMYLOIDOSIS

low

voltages

on limb

leads

pseudo-

infarct

patterns

“Electrical” mass (ECG)

“Structural”

mass (ECHO) Hypertensive

patientsNormal

subjects

Cardiac AL

patients

Courtesy of Stefano Perlini, modified

(Dis)proportion

between

LV thickness and

QRS voltage

ECHO

RV hypertrophy

Thickened MV leaflets

Preserved LVEF

Thickened IA septum

LA dilation

Marked symmetric LVH

Mild pericardial effusion

Reduced e’ velocity

Pseudonormal mitral pattern

Increased PASP

Increased E/e’

Reduced A wave

Increased E/e’ (septal >>> lateral)

Restrictive mitral pattern

Increased PASP

Apical sparing

ECHO

Differential diagnosis of LVH: the real challenge!

Age

Fre

qu

en

cy

Hypertension

Hypertrophic cardiomyopathy

Aortic

stenosis

Athlete heart

Mithocondrial

diseases

Pompe

Fabry

Danon

Amyloidosis

Modified from Kobo et al. Curr Cardiol Rep 2017

Maurizi et al INT J CARD 2019

HCM vs. cardiac amyloidosis343 patients aged ≥40 years initially referred for a diagnosis of HCM

Canepa M, Olivotto I et al. Submitted.

Age at diagnosis is increasing in HCM

<197

8

1979

-198

3

1984

-198

8

1989

-199

3

1994

-199

8

1999

-200

3

2004

-200

8

2009

-201

3

2014

-201

8

0

10

20

30

40

50

60

70

Year Cohort

Ag

e a

t D

iag

no

sis

(y

ea

rs)

Age at diagnosis in US and Non-US sites

Overall

US Cohort

Non-US Cohort

p<0.001

1111

*

1254 677611219 305148 19093Overall Share Population

513 719 38726786 12333 5731US

598 535 290344133 182115 13362Non-US

<1978

1979

-198

3

1984

-198

8

1989

-199

3

1994

-199

8

1999

-200

3

2004

-200

8

2009

-201

3

2014

-201

8

0

20

40

60

80

100

Year Cohort

Po

pu

lati

on

(%

) <40

40-60

>60

Age Groups

p<0.001

Temporal distribution of age groups at diagnosis

<1978

1979

-198

3

1984

-198

8

1989

-199

3

1994

-199

8

1999

-200

3

2004

-200

8

2009

-201

3

2014

-201

8

0

10

20

30

40

50

60

70

Year Cohort

Ag

e a

t D

iag

no

sis

(years

)

Men

Women

p<0.001

704 762 412379133 19394 11964Men

407 492 26523286 11254 7129Women

*

Age at diagnosis by gender

<1978

1979

-198

3

1984

-198

8

1989

-199

3

1994

-199

8

1999

-200

3

2004

-200

8

2009

-201

3

2014

-201

8

0

20

40

60

80

100

Year Cohort

Po

pu

lati

on

(%

)

Men

Women

p=0.861

Temporal distribution of gender at diagnosis

<197

8

1979

-198

3

1984

-198

8

1989

-199

3

1994

-199

8

1999

-200

3

2004

-200

8

2009

-201

3

2014

-201

8

0

10

20

30

40

50

60

70

Year Cohort

Ag

e a

t D

iag

no

sis

(years

)

SARC +

SARC -

p<0.001

SARC VUS

300 150330112 20067 885543P/LP

136 778720 6113 2288VUS

416 16632481 18540 48259G-

*

Age at diagnosis by genetic status

<197

8

1979

-198

3

1984

-198

8

1989

-199

3

1994

-199

8

1999

-200

3

2004

-200

8

2009

-201

3

2014

-201

8

0

20

40

60

80

100

Year Cohort

Po

pu

lati

on

(%

) SARC +

SARC VUS

SARC-

p<0.001

Temporal distribution of genetic status at diagnosis

A B C

SHaRe Registry

7,286 HCM patients

from 11 centers

worldwide

Scully et al. JACC 2018; Mohammed et al. JACC HF 2014; Castano et al. Eur Heart J 2017

More than 10% (and up to 30%) of patients >75 years of age

with either HFpEF or aortic stenosis undergoing AVR/TAVI

have ATTR-CA

HFpEF & AO STEN vs. cardiac amyloidosis

E.T., 83 years old, male, AORTIC STENOSISE.C., 84 years old, male, HFpEF

ATTR-CM: an evolving disease

Until few years ago …

❖Difficult diagnosis, biopsy needed

Since 2018 …

➢Non-invasive diagnosis possible

❖No treatment available

➢New treatments available

THERAPY

Therapeutic approaches to ATTR-CM

All-cause mortality

Maurer et al. ATTR-ACT trial. NEJM 2018

Key Secondary Endpoints

Maurer et al. ATTR-ACT trial. NEJM 2018

Pre-specified Subgroup Analysis

Maurer et al. ATTR-ACT trial. NEJM 2018

ATTR-ACT trial

n (%)

Real-world

n (%)

P value

Total population 264 (tafamidis pooled) 507 (Italian cohort)

Age 74.5±7.2 74.5±8.7 0.988

Males 241 (91.3) 429 (84.6) <0.0001

Comorbidities

Hypertension

Diabetes

145 (54.9)

20 (7.6)

301 (59.4)

67 (13.2)

0.021

<0.0001

TTR genotype

ATTRv

ATTRwt

Genetics not performed

63 (23.9)

201 (76.6)

0 (0)

120 (23.7)

368 (72.6)

19 (3.7)

0.458

0.070

NYHA class

I

II

III

IV

24 (9.1)

162 (61.4)

78 (29.5)

0 (0)

106 (20.9)

287 (56.6)

112 (22.1)

2 (0.4)

<0.0001

0.026

<0.001

NT-proBNP (pg/ml) 2995.9 (1751.5-4861.5) 2547 (1333-4578) <0.001

Creatinine clearance (ml/min) 58.8±17.9 66.5±25.5 <0.0001

Troponin I (ng/ml) 0.14 (0.09-0.20) 0.02 (0.01-0.07) <0.0001

ATTR

-AC

T t

ria

l vs. R

ea

l-w

orl

d p

ati

en

ts

Canepa et al. EJHF 2019

ATTR-CM pharmacologic treatment … as of today

❑ ATTR-wt cardiomyopathy: none!

❑ ATTR-m cardiomyopathy:

➢Without neurological involvement: none!

➢With neurological involvement:

o tafamidis (stabilizer)

o patisiran (synthesis suppression)

o inotersen (synthesis suppression)

Phe 64 Leu

NEURO

Glu 89 Gln

NEURO/CARDIO

Val 30 Met (LO)

NEURO/CARDIO

Ile 68 Leu

CARDIO

Data from Dr. Marco Di Gerolamo

TTR gene mutations

Journal of Cardiovascular Translational Research

December 2019, Volume 12, Issue 6, pp 514–516

ATTR-CM pharmacologic treatment … in the meantime

❑ Diuretic, diuretic, diuretic!

❑ Beta-blocker (?)

➢Restrictive physiology

➢Chronotropic incompetence

❑ Anticoagulant (?)

CONCLUSIONS

THE DISEASE IS

RARE

THE DIAGNOSIS IS

DIFFICULT

CONCLUSION 1: time to break the circle

Tini, Olivotto, Canepa. Eur Heart Journal 2019

CONCLUSION 2: a mechanism of HFpEF

ATTR-CM

Comorbidities

CONCLUSION 3: worthy diagnosis

CONCLUSION 3: worthy diagnosis

GINEVRA

RIZZOLA

GIACOMO

TINI

PIER FILIPPO

VIANELLO

GIOVANNI

LA MALFANEUROLOGIA: Marina Grandis, Chiara Gemelli

GENETICA: Paola Mandich, Lucia Trevisan

EMATOLOGIA: Michele Cea

MEDICINA NUCLEARE: Selene Capitanio

PAVIA: Paolo Milani, Stefano Perlini, Giovanni Palladini

FIRENZE: Francesco Capelli, Federico Perfetto

ROMA: Beatrice Musumeci, Camillo Autore

BOLOGNA: Claudio Rapezzi

SAVE

THE

DATE !