L’AMILOIDOSI CARDIACA DA TRANSTIRETINA (ATTR-CM)SOSPETTA DIAGNOSTICA

COS’È L’AMILOIDOSI

Le amiloidosi sono malattie causate dalla deposizione di materiale proteico, denominato amiloide, negli spazi tra le cellule.1

L’amiloide si forma quando molecole proteiche normali o mutate si ripiegano in modo anomalo, si uniscono tra loro e formano delle fibrille insolubili.1

I depositi di amiloide danneggiano le cellule intorno a cui sono depositate causando diversi disturbi.1

La differenziazione clinica tra ATTR e AL è importante, poiché il loro decorso clinico è diverso.3

TIPI PIÙ COMUNI DI AMILOIDOSI CARDIACA

AMILOIDOSI DA TRANSTIRETINA (ATTR)2

AMILOIDOSI DA CATENE LEGGERE DELLE IMMUNOGLOBULINE (AL)2

ATTR WILD-TYPE (wtATTR)3

ATTR EREDITARIA (hATTR)3 NOTA ANCHE COME VARIANTE4

(TTR)–related

amyloidosis (wt-ATTR

). Indeed,

degenerative

AS and wt-ATTRshare a common

demographic and clinical

profile.Data from

postmortem studiesin unselec

ted subjectsindicate

a prevalence of cardi

ac amyloidosis of 22%

to 25% in

subjectsolder th

an 80 years of age (3).

TTR-related cardiac

amyloidosis can current

ly be

accurately identifi

ed by scintigraphy with bone-

seekingtracers

(4). A recent study with technetium–

99m-3,3-diphospho

no-1,2propano

dicarboxylic acid

(99mTc-DPD

) scintigraphy in 12,400

subjectsfound a

prevalence of strong,

unexpected myocardi

al tracer

uptake,suggest

ive of cardiacamyloidos

is, in w1.4%

of subjects older th

an 80 years of age (5).

To clinically investig

ate the coexistence of cardi

ac

amyloidosis in elderly

patientswith AS referred

for

aortic valve replacement (surgica

l or transcatheter),

we prospectively evaluat

ed with99mTc-DPD

scintig-

raphy all patientswith degene

rative AS and 1 or

more of the following echocardiograp

hic “red flags”:

increased thickne

ss of atrioventricu

lar valves, inte

ra-

trial septum or right

ventricular free

wall, pericardial

effusion, and myocardi

al granular spar

kling.

Of the 43patients

referredwithAS (betw

eenOctober

2014 and January2015),

5 had echocardiograp

hic

“red flags” and underwent

99mTc-DPDscintigr

aphy

before a final decision regardin

g treatment was made.

The scan showed strongmyocardi

al uptakein all

patients. All the

n underwent end

omyocardial biops

y,

which consistently demonstrate

d TTR-related amy-

loid infiltration. Genetic

analysisexclude

d TTR

gene mutations, and wt-ATTR

was diagnosed in all

5 patients.

Of the 5 patientswith wt-ATTR

, only 1 was female

(median age 84 years; range 76 to 90 years),

and all

had advanced heart failure

(New York Heart Associ-

ation functional class III/IV).

Interestingly, 3 had a

historyof carpal t

unnel syndrom

e (bilateral in 2 pa-

tients).All had marked symmetrical

left ventricular

(LV) hypertrophy (median wall thickne

ss, 18 mm;

range 16 to 21 mm) with a calculated aortic valve

area #0.6 cm2/m

2. In 4 of 5 patients, a low flow–low

gradient conditio

n was present(with reduced

LV

ejectionfraction

in 2 patients). Remarkably

, all

echocardiograp

hic “red flags” were presentin 3 of 5

patients, and longitu

dinal function was depress

ed in

all patients. A disprop

ortionbetween echocar

dio-

graphicLV “hypert

rophy”and normal QRS voltage

s

was presentin 4 patients

(only 1 satisfiedelectro-

cardiographic

criteriafor LV hypertr

ophy).All pa-

tients underwent balloon

aortic valvuloplasty with a

“bridgeto decision

” strategyand are current

ly un-

dergoing a clinical

follow-up. Figure 1 summarizes th

e

instrumental fin

dings of a typicalcase.

This small preliminary study found that the coex-

istenceof degene

rative AS and wt-ATTR(a poten-

tially dangerous conditio

n in patients undergo

ing

aortic valve replacement) can be suspect

ed on the

basis of clinical and echocar

diographic elements and

can be effectively diagnos

ed by99mTc-DPD

scintig-

raphy.The study cannot

providedata on disease

prevalence and test sensitiv

ity but suggests that

particular attentio

n shouldbe paid to patients

with

echocardiograp

hic signs of myocardial infiltrat

ion

and/ora mismatch between LV wall thickne

ss and

QRS voltages and/or

low flow–low gradient and

depressed longitu

dinal myocardial functio

n. Larger

prospective studies

are neededto establis

h in which

patientswith AS to search for cardiac

amyloidosis as

well as how to use this information in the treatment

decision-making process

.

Simone Longhi,MD

Massimiliano Lorenzini, MD

ChristianGagliard

i, MD

AgneseMilandri, M

D

AntonioMarzocchi

, MD

Cinzia Marrozzini, MD

Francesco Saia, MD, PhD

FIGURE 1 PatientWith Aortic Stenosis

and Wild-TypeTTR–Re

lated Amyloidosis

(A and B) Echocardiogra

m showing “red flags” for cardiac amyloidosis

: ventricular

myocardium granular

sparkling, atriove

ntricularvalve thickenin

g, and mild pericardial

effusion. (C). Ele

ctrocardiogram: typical

signs of severe aortic stenosis

(left ventricular

hypertrophy) are

absent.(D) Tech

netium–99m-3,3-diphosphon

o-1,2 propanodicarbox

ylic

acid scintigraphy showing strong myocardia

l traceruptake.

(E and F) Endomyocardia

l

biopsy with TTR-related amyloid infiltrati

on. (E) Hematoxylin

-eosin, Congo red staining.

(F) Immunohistochemistry with anti-TTR

antibodies. TTR

¼ transthyretin.

Letters to the Editor

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 9 , N O . 3 , 2 0 1 6

M A R C H 2 0 1 6 : 3 2 1 – 3 1

326

(TTR)–related

amyloidosis (wt-ATTR)

. Indeed,

degenerative AS and wt-ATTR

share a common

demographic and clinical

profile.Data from

postmortem studiesin unselec

ted subjectsindicate

a prevalence of cardi

ac amyloidosis of 22% to 25% in

subjectsolder th

an 80 years of age (3).

TTR-related cardiac

amyloidosis can currentl

y be

accurately identifie

d by scintigraphy with bone-

seekingtracers

(4). A recent study with technetium–

99m-3,3-diphosphon

o-1,2 propanodicarbox

ylic acid

(99mTc-DPD)

scintigraphy in 12,400 subjects

found a

prevalence of strong,

unexpected myocardia

l tracer

uptake,suggest

ive of cardiacamyloidosi

s, in w1.4%

of subjects older th

an 80 years of age (5).

To clinically investig

ate the coexistence of cardi

ac

amyloidosis in elderly

patientswith AS referred

for

aortic valve replacement (surgica

l or transcatheter),

we prospectively evaluate

d with99mTc-DPD

scintig-

raphy all patientswith degener

ative AS and 1 or

more of the following echocardiograp

hic “red flags”:

increased thicknes

s of atrioventricul

ar valves, intera

-

trial septum or right

ventricular free

wall, pericardial

effusion, and myocardia

l granular spark

ling.

Of the 43 patients r

eferredwithAS (betw

eenOctober

2014 and January2015), 5 had echocar

diographic

“red flags” and underwent

99mTc-DPDscintigra

phy

before a final decision regardin

g treatment was made.

The scan showed strongmyocardia

l uptakein all

patients. All the

n underwent end

omyocardial biopsy

,

which consistently demonstrate

d TTR-related amy-

loid infiltration. Genetic

analysisexclude

d TTR

gene mutations, and wt-ATTR

was diagnosed in all

5 patients.

Of the 5 patientswith wt-ATTR,

only 1 was female

(median age 84 years; range 76 to 90 years), a

nd all

had advanced heart failure (New York Heart Associ-

ation functional class III/IV).

Interestingly, 3 had a

historyof carpal t

unnel syndrom

e (bilateral in 2 pa-

tients).All had marked symmetrical left ventricu

lar

(LV) hypertrophy (median wall thicknes

s, 18 mm;

range 16 to 21 mm) with a calculated aortic valve

area #0.6 cm2/m

2. In 4 of 5 patients, a low flow–low

gradient conditio

n was present(with reduced

LV

ejectionfraction

in 2 patients). Remarkably,

all

echocardiograp

hic “red flags” were presentin 3 of 5

patients, and longitud

inal function was depress

ed in

all patients. A disprop

ortion between echocardio-

graphicLV “hypert

rophy”and normal QRS voltages

was presentin 4 patients

(only 1 satisfiedelectro-

cardiographic criteria

for LV hypertrophy). All pa-

tients underwent balloon

aortic valvuloplasty with a

“bridgeto decision

” strategyand are currentl

y un-

dergoing a clinical

follow-up. Figure 1 summarizes th

e

instrumental fin

dings of a typical case.

This small preliminary study found that the coex-

istenceof degener

ative AS and wt-ATTR(a poten-

tially dangerous conditio

n in patientsundergo

ing

aortic valve replacement) can be suspect

ed on the

basis of clinical and echocar

diographic elements and

can be effectively diagnos

ed by99mTc-DPD

scintig-

raphy.The study cannot

providedata on disease

prevalence and test sensitiv

ity but suggests that

particular attentio

n shouldbe paid to patients

with

echocardiograp

hic signs of myocardial infiltrat

ion

and/ora mismatch between LV wall thicknes

s and

QRS voltagesand/or

low flow–low gradient and

depressed longitud

inal myocardial function

. Larger

prospective studies

are neededto establis

h in which

patientswith AS to search for cardiac

amyloidosis as

well as how to use this information in the treatment

decision-making process.

Simone Longhi, MD

Massimiliano Lorenzini, MD

ChristianGagliard

i, MD

Agnese Milandri, MD

AntonioMarzocchi,

MD

Cinzia Marrozzini, MD

Francesco Saia, MD, PhD

FIGURE 1 PatientWith Aortic Stenosis

and Wild-TypeTTR–Rel

ated Amyloidosis

(A and B) Echocardiogra

m showing “red flags” for cardiac amyloidosis

: ventricular

myocardium granular

sparkling, atriove

ntricularvalve thickenin

g, and mild pericardial

effusion.(C). Elec

trocardiogram: typical

signs of severeaortic stenosis

(left ventricular

hypertrophy) are

absent. (D) Techn

etium–99m-3,3-diphosphono

-1,2 propanodicarbox

ylic

acid scintigraphy showing strong myocardia

l tracer uptake. (E

and F) Endomyocardia

l

biopsy with TTR-related amyloid infiltratio

n. (E) Hematoxylin-

eosin, Congo red staining.

(F) Immunohistochemistry with anti-TTR

antibodies. TTR ¼ transthy

retin.

Letters to the Editor

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 9 , N O . 3 , 2 0 1 6

M A R C H 2 0 1 6 : 3 2 1 – 3 1

326

amyloid fibril composition

(Fig. 1)[11]. V

30M is the only

pathogenic mutation

that haslarge foci aro

und the world,

especially in parts of

Portugal, Japan

and northern Sweden

[5, 6, 8, 11]. T

he prominent features of Portugu

ese and

Japanese endemic Val30M

et are sensorimotor polyneu

-

ropathy—usually

startingin the mid-thirti

es—and auto-

nomic neuropathy [5, 6, 8

, 11]. Family history

is generally

positive, as the conditio

n is inherited in an autosom

al

dominant fashion. C

onduction disturba

nces are relatively

frequent; on the contrary

, cardiomyopathy

is rare,but can

lead to heart failure as

diseaseprogres

ses [5,6, 8, 11

]. On

the other hand, the clinical

profileof Swedis

h endemic

Val30Met ATT

R is characterised by older age at onse

t,

lower (about2 %) penetra

nce and a slowerdisease

pro-

gression[5, 6, 8

, 11]. Non-ende

mic forms of Va

l30Met are

found in many countries and have a much greater

pheno-

typic variability. A

common characteristic

is lower age-

relatedpenetra

nce with an apparently negativ

e family

history.Cardiom

yopathytends to

be more frequent tha

n in

endemic Val30Met, wherea

s autonomic dysfunc

tion is

generally milder [5, 6, 8

, 11]. Non-Val3

0Met mutations

have been reportedin differen

t European countrie

s, in Ja-

pan, inNorth and South America [5, 6, 8

, 11]. Many mu-

tationstend to cluster

in certainethnic

groupsand in

limited geographical ar

eas, inrelation

to the existence of

common founders (‘‘priva

te mutations’’). In general

, a

relatively tight genotyp

e–phenotype associa

tion can be

found (Fig. 2)[12]. S

ome mutationsare associa

ted with

both neurological and cardiac

manifestations,

whereas

otherslead to an exclusiv

ely neurological d

isease and a

small number are associated with an exclusiv

ely car-

diological phen

otype. In ATTR,

particularly in Val30M

et-

relatedform, age at onse

t is quite variableand unknow

n

factors,other th

an the mutation,may be involve

d, includ-

ing genderof the transmitting parent

[11]. In patients

originating from Portugu

ese, Swedish and some Japanes

e

kindreds, age at onse

t is significantly later w

hen the mu-

tation is inherited from the mother than from the father.

Patientgender

can also influence cardiac

phenotype since

female genderseems to provide

some protection from

myocardial invo

lvement, atleast be

fore menopause onset

Table 2 Factorsleading

to misdiagnosis

Physician-rela

ted factors

Fragmented knowledge among differen

t specialties an

d subspecialties

Shortage of centr

es andexperts

dedicated to speciali

sed diseasemanagem

ent

Common misconceptions a

bout diagnosin

g and typingamyloid

• Low voltageis not s

ensitivenor spe

cific findingin isolatio

n to excludethe presenc

e of cardiac amyloidos

is

• Serumprotein

electrophoresis

is not asufficie

nt screening test to e

xcludethe pres

ence ofa plasm

a cell disorder

than can cause

AL amyloid

• A fat padbiopsy

has a sensitivity for AL

amyloid of 70 % at bestand is posit

ive in\ 50 % of subjects with

ATTRCA

Erroneous belie

f it is an untreata

ble disease

Disease-related

factors

Rarity

Intrinsic phenoty

pic heterogeneity

Genotypic heterog

eneity in ATTR

Necessity of targe

t organtissue histolog

ical diagnosis

in the vast majorityof case

s

Fig. 1Main known

determinantsof phenoty

pic heterogeneity

in

ATTR.Modified

from Rapezzi et al.,

Nat Rev Cardiol

2010Fig. 2

Genotype–phe

notypecorrelat

ion in ATTR.Modified

from

Rapezzi et al.,

Eur Heart J 20

13

Heart Fail Rev

(2015)20:117–

124

119

123

INDIVIDUARE L’AMILOIDOSI CARDIACA DA TRANSTIRETINA (ATTR-CM)

Scintigrafia nucleare con traccianti ossei Uno strumento diagnostico non invasivo e facilmente disponibile con

elevata sensibilità e specificità per la ATTR-CM quando combinato con i test* per escludere l’amiloidosi AL.5

Utilizza traccianti ossei radioattivi coniugati all’isotopo tecnezio-99 [99mTc]: il tecnezio 99mdifosfonato [99mTc-DPD], il tecnezio 99midrossi-metilene-difosfonato [99mTc-HMDP] o il tecnezio 99mpirofosfato [99mTc-PYP].5

Biopsia endomiocardica Per la diagnosi di amiloidosi cardiaca può essere necessario un esame

istologico positivo alla colorazione rosso Congo con birifrangenza verde mela (alla luce polarizzata del microscopio elettronico).5

Dopo la diagnosi di amiloidosi cardiaca si raccomandano ulteriori esami per la determinazione del tipo di amiloide.5

Il rischio di complicanze e la necessità di centri e personale specializzati possono contribuire a ritardare la diagnosi.5

Test genetico Usato per determinare se la malattia è ereditaria a causa di una

mutazione nel gene TTR2* Una volta confermata la ATTR-CM si raccomandano consulenza

genetica e sequenziamento genico.6

*Esclusione della AL: test per individuare la presenza di proteina monoclonale mediante Immunofissazione sierica e urinaria delle 24h + ricerca e rapporto delle catene leggere libere nel siero.

UN ALGORITMO DIAGNOSTICO PER I PAZIENTI CON SOSPETTA ATTR-CM1

Uno studio multicentrico internazionale ha dimostrato il 99% di sensibilità per la scintigrafia nucleare ossea nella diagnosi di ATTR-CM (grado di captazione miocardica del tracciante osseo variabile da 1 a 3, secondo una scala visiva) in associazione a test negativi per l’amiloidosi AL. Un’analisi separata nell’ambito dello stesso studio ha dimostrato il 100% di specificità in caso di grado 2-3 e contemporanea assenza di componenti monoclonali sieriche e urinarie e alterazioni del rapporto delle catene leggere libere§ 5

GRADO 0Indica assenza

di captazione cardiaca del tracciante

GRADO 1Indica una lieve

captazione cardiaca di tracciante, inferiore alla

captazione ossea

GRADO 2Indica una moderata captazione cardiaca

di tracciante, pari alla captazione

ossea

GRADO 3Indica una elevata

captazione cardiaca di tracciante, superiore alla

captazione ossea

Questo algoritmo è basato sull’uso del seguente sistema di grading ottenuto con la scintigrafia nucleare ossea1

§Studio multicentrico condotto per determinare il valore diagnostico della scintigrafia ossea nei pazienti con ATTR-CM. Su 1.217 pazienti valutabili, 374 sono stati sottoposti a biopsia endomiocardica, mentre per 843 la presenza e il tipo o l’assenza di amiloide sono stati diagnosticati sulla base dell’esame istologico extracardiaco associato a ecocardiogramma con o senza risonanza magnetica cardiaca (RMC).

Fig. 1, Ref. 7

Insufficienza cardiaca, sincope o alterazioni del ritmo associati ad ecocardiogramma e/o risonanza magnetica cardiaca (RM Cuore) che suggeriscono/indicano amiloidosi cardiaca

Scintigrafia ossea con 99mTc-DPD/HMDP/PYP

Grado 0 Grado 1 Grado 2 e 3

Immunofissazione sierica + immunofissazione urinaria + dosaggio delle catene leggere libere nel siero (test Freelite).

Presente proteina monoclonale?

NO SI SI NO SI NO

Amiloidosi cardiaca AL/ATTR

improbabile

Esaminare/Richiedere RMC

Necessaria valutazione specialistica per la diagnosi: conferma

istologica e tipizzazione dell’amiloide

Amiloidosi cardiaca ATTR

Genotipizzazione TTR

Amiloidosi cardiaca (AL/AApoAI/ATTR/altra)

Amiloidosi ATTR

ereditaria

Amiloidosi ATTR

wild-type

Riprodotto con il permesso di Wolters Kluwer Health, Inc.

Algoritmo diagnostico proposto da Gilmore5

La scintigrafia nucleare con traccianti ossei per diagnosticare l’amiloidosi cardiaca (ATTR-CM)

Eleven patients with myocardial uptake of 99mTc-DPDagreed to undergo 99mTc-MDP scintigraphy. The visualscore for 99mTc-MDP myocardial uptake was 0 in all ofthese patients. A representative example of differences inmyocardial uptake of the two tracers can be seen in Figure3. The visual score for 99mTc-MDP soft tissue uptake was 0in 8 patients and 1 in the remaining 3.Diagnostic accuracy of 99mTc-DPD scintigraphy fordifferentiation of TTR-related and AL cardiac amyloid-osis. We assessed the diagnostic accuracy of 99mTc-DPDscintigraphy (visual score �0) for differentiation of TTR-related and AL cardiac amyloidosis using genotyping/immunohistochemistry as the reference technique. Within oursubpopulation of amyloidosis patients with echocardiographicevidence of cardiac involvement (groups A and B), sensitivityand specificity of 99mTc-DPD scintigraphy were both 100%.Diagnostic accuracy of 99mTc-DPD scintigraphy fordetection of amyloidotic cardiomyopathy within differentetiologic settings. We also considered the diagnostic ac-curacy of a scintigraphy visual score �0 between each of thetwo groups of patients and the control patients for detection

of cardiac amyloidosis using echocardiography as the refer-ence standard. Sensitivity and specificity of scintigraphywere both 100% for group A (TTR-related patients). Bycontrast, for group B (AL patients), sensitivity was 0% andspecificity was 100%. Thus, the overall accuracy for detec-tion of amyloid of both types was only 50%. These findingsfurther illustrate the concept that etiology can be a majorcause of variability in the diagnostic performance of 99mTc-DPD scintigraphy.Patterns of myocardial uptake of 99mTc-DPD. All butone of the group A patients had widespread involvement ofall myocardial segments (Fig. 4A), whereas the remainingpatient showed localized septal accumulation (Fig. 4B).These observations paralleled the patterns of increased wallthickness visible at echocardiography (Fig. 4).99mTc-DPD scintigraphy findings in soft tissue. Regard-ing extracardiac uptake of 99mTc-DPD, at semiquantitativeanalysis whole-body retention was significantly higher inboth groups A and B with respect to controls (Table 2, Fig.2C). The increased uptake of 99mTc-DPD was visuallydetectable at the muscular and/or splanchnic level in 13 of

Figure 1. Representative examples illustrating the spectrum of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) uptake among patientswith transthyretin (TTR)-related or monoclonal immunoglobulin light-chain (AL) cardiac amyloidosis and unaffected controls (top row � whole-bodyscans, anterior view; bottom row � cross sectional views of cardiac single-photon emission computed tomography in the same patients). (A) Unaffectedcontrol subject without visually detectable uptake. (B) Patient with AL amyloidosis and echocardiographic documentation of cardiac involvement withoutany visually detectable sign of myocardial 99mTc-DPD uptake; mild uptake of the tracer is visible only at the soft tissue level. (C and D) Two patients withTTR-related amyloidosis and echocardiographic documentation of cardiac involvement, both showing strong myocardial 99mTc-DPD uptake (with absentbone uptake); in one of the patients (D), splanchnic uptake is also visible.

1079JACC Vol. 46, No. 6, 2005 Perugini et al.September 20, 2005:1076–84 Etiologic Diagnosis of Cardiac Amyloidosis

Eleven patients with myocardial uptake of 99mTc-DPDagreed to undergo 99mTc-MDP scintigraphy. The visualscore for 99mTc-MDP myocardial uptake was 0 in all ofthese patients. A representative example of differences inmyocardial uptake of the two tracers can be seen in Figure3. The visual score for 99mTc-MDP soft tissue uptake was 0in 8 patients and 1 in the remaining 3.Diagnostic accuracy of 99mTc-DPD scintigraphy fordifferentiation of TTR-related and AL cardiac amyloid-osis. We assessed the diagnostic accuracy of 99mTc-DPDscintigraphy (visual score �0) for differentiation of TTR-related and AL cardiac amyloidosis using genotyping/immunohistochemistry as the reference technique. Within oursubpopulation of amyloidosis patients with echocardiographicevidence of cardiac involvement (groups A and B), sensitivityand specificity of 99mTc-DPD scintigraphy were both 100%.Diagnostic accuracy of 99mTc-DPD scintigraphy fordetection of amyloidotic cardiomyopathy within differentetiologic settings. We also considered the diagnostic ac-curacy of a scintigraphy visual score �0 between each of thetwo groups of patients and the control patients for detection

of cardiac amyloidosis using echocardiography as the refer-ence standard. Sensitivity and specificity of scintigraphywere both 100% for group A (TTR-related patients). Bycontrast, for group B (AL patients), sensitivity was 0% andspecificity was 100%. Thus, the overall accuracy for detec-tion of amyloid of both types was only 50%. These findingsfurther illustrate the concept that etiology can be a majorcause of variability in the diagnostic performance of 99mTc-DPD scintigraphy.Patterns of myocardial uptake of 99mTc-DPD. All butone of the group A patients had widespread involvement ofall myocardial segments (Fig. 4A), whereas the remainingpatient showed localized septal accumulation (Fig. 4B).These observations paralleled the patterns of increased wallthickness visible at echocardiography (Fig. 4).99mTc-DPD scintigraphy findings in soft tissue. Regard-ing extracardiac uptake of 99mTc-DPD, at semiquantitativeanalysis whole-body retention was significantly higher inboth groups A and B with respect to controls (Table 2, Fig.2C). The increased uptake of 99mTc-DPD was visuallydetectable at the muscular and/or splanchnic level in 13 of

Figure 1. Representative examples illustrating the spectrum of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) uptake among patientswith transthyretin (TTR)-related or monoclonal immunoglobulin light-chain (AL) cardiac amyloidosis and unaffected controls (top row � whole-bodyscans, anterior view; bottom row � cross sectional views of cardiac single-photon emission computed tomography in the same patients). (A) Unaffectedcontrol subject without visually detectable uptake. (B) Patient with AL amyloidosis and echocardiographic documentation of cardiac involvement withoutany visually detectable sign of myocardial 99mTc-DPD uptake; mild uptake of the tracer is visible only at the soft tissue level. (C and D) Two patients withTTR-related amyloidosis and echocardiographic documentation of cardiac involvement, both showing strong myocardial 99mTc-DPD uptake (with absentbone uptake); in one of the patients (D), splanchnic uptake is also visible.

1079JACC Vol. 46, No. 6, 2005 Perugini et al.September 20, 2005:1076–84 Etiologic Diagnosis of Cardiac Amyloidosis

L’AMILOIDOSI CARDIACA DA TRANSTIRETINA (ATTR-CM):UNA NUOVA ERA PER LA DIAGNOSI NON INVASIVA

BIBLIOGRAFIA

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2. Ruberg FL, Berk JL. Transthyretin (TTR) Cardiac Amyloidosis. Circulation. 2012;126:1286–1300

3. Rapezzi C et al,. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009 Sep 29;120(13):1203-12. doi: 10.1161/CIRCULATIONAHA.108.843334. Epub 2009 Sep 14.

4. Benson MD et al,. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid. 2018 Dec;25(4):215-219. doi: 10.1080/13506129.2018.1549825. Epub 2019 Jan 7.

5. Gilmore JD et al,. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12. doi: 10.1161/CIRCULATIONAHA.116.021612. Epub 2016 Apr 22.

6. Maurer MS et al,. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation. 2017 Apr 4;135(14):1357-1377. doi: 10.1161/CIRCULATIONAHA.116.024438.

7. Perugini E et al,. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol.2005 Sep 20;46(6):1076-84.

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