amiloidosi: dalla fisiopatologia alle nuove terapie · amiloidosi: dalla fisiopatologia alle nuove...
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Amiloidosi: dalla fisiopatologiaalle nuove terapie
Marco CanepaUniversità degli Studi di Genova
IRCCS Policlinico San Martino, Genova
Ambulatorio Scompenso Cardiaco/
Cardiomiopatia Ipertrofica
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
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 !