TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM)

ATTR-CM: The Disease•ATTR-CMisarareconditionthatislife-threatening, underrecognized,andunderdiagnosed1-6

Suspect the Signs of ATTR-CM• ThediagnosisofATTR-CMisoftendelayedormissed1-3

Detect ATTR-CM Utilizing Nuclear Scintigraphy• ToolsusedtodiagnoseATTR-CMincludenuclearscintigraphy(eg,PYPcardiacimaging),endomyocardialbiopsy(EMB),andgenetictesting4,7-10

PYP=99mTc-pyrophosphate.

A LIFE-THREATENING DISEASE THAT CAN GO UNDETECTED

UNDERSTANDING TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM)

UNDERSTANDING ATTR-CMAmyloidosisisagroupofdiseasesinwhichamyloidfibrilsdepositintotheextracellularspaceoftheheart. Theamyloidfibrilsareformedbyanaggregationofmisfoldedproteins.11Themostcommonamyloidfibrilproteinsthatcaninfiltratetheheartandleadtocardiacamyloidosis12are immunoglobulin light chain (AL),

a hematological emergency, and transthyretin (ATTR).4,7,11,12

AsforATTR-CMspecifically,itisfoundmostlyinolderpatients,inwhommisfoldedtransthyretinproteinsdepositintheheart.13Thisrareconditionislife-threatening,underrecognized,andunderdiagnosed.1-6

COMMON SIGNS AND SYMPTOMS IN wtATTR AND hATTR1-3,11,19-22*

A CLOSER LOOK AT WILD-TYPE AND HEREDITARY ATTR-CM

WILD-TYPE ATTR-CMWild-typeATTR-CM(wtATTR)isidiopathic1andisnotconsideredtobeahereditarydisease.5It is thought to account for the majority of all ATTR-CM cases.3

SOME PATIENT CONSIDERATIONS• Ethnicity:predominantlywhite1,3

• Mostlymen1-3

• Symptomonsettypicallyovertheageof60years15

• Heartfailure1-3

• Cardiacarrhythmias,particularlyatrialfibrillation1-4

• Historyofcarpaltunnelsyndrome,oftenbilateral1,2,16

PROGNOSIS• Withouttreatment,mediansurvival: ~3.5years1,2,16

HEREDITARY ATTR-CMHereditaryATTR-CM(hATTR)*occursduetoamutationintheTTRgene.5IntheUnitedStates,themostcommonmutationcausingATTRisthevaline-to-isoleucinesubstitutionatposition122(V122I).3ThismutationaffectsalmostexclusivelytheAfricanAmericanpopulation,withaprevalenceofabout3-4%.4,17Notallpatientswhocarrythismutationwillgoontohaveclinicalsignsandsymptomsofthisdisease.*AlsoknownasvariantATTR(ATTRv).14

SOME PATIENT CONSIDERATIONS• AfricanAmerican,African,or Afro-Caribbeandescent3,4

• Menandwomen3

• Symptomonsetmayoccuras earlyas50-60yearsofage15,18

• Heartfailure3

• Neurologicalsymptoms(peripheralandautonomic)3

• Gastrointestinalsymptoms3

• Historyofcarpaltunnelsyndrome,oftenbilateral3

PROGNOSIS• Withouttreatment,mediansurvival:~2to3years4

Cardiac• Fatigue• Shortnessofbreath• Edema

• Arrhythmias• HFpEF• Aorticstenosis

SoftTissue • Lumbarstenosis• Bicepstendonrupture

GI • Diarrhea• Constipation

• Nausea• Earlysatiety

Neurologic• CarpalTunnel

Syndrome• Peripheralneuropathy

• Orthostasis• Weakness

CTS,carpaltunnelsyndrome;GI,gastrointestinal;hATTR,hereditaryATTR;HFpEF,heartfailurewithpreservedejectionfraction;wtATTR,wild-typeATTR,previouslyknownassenilecardiacamyloidosis,senilesystemicamyloidosis,orage-relatedamyloidosis.*AlsoknownasvariantATTR.14

Cardiac

Lumbar stenosisNeurologic/CTS

Cardiac

Neurologic/CTS

GI

wtATTR hATTR*

Most Common Types of Cardiac Amyloidosis

Immunoglobulin l ight chain amyloidosis (AL)12Transthyretin amyloidosis (ATTR)12

Wild-type ATTR(wtATTR)12

Previously known as senile or age-related

Hereditary ATTR(hATTR)12

Also known as variant14

ATTR-CM: The Disease

IT IS CRITICAL TO CLINICALLY DIFFERENTIATE BETWEEN ATTR AND AL, AS AL REQUIRES IMMEDIATE TREATMENT AND HAS A DIFFERENT CLINICAL COURSE.

32

HIDDEN IN PLAIN SIGHT

HFpEF INTOLERANCEDISCORDANCEDIAGNOSISECHONERVOUS SYSTEM

heart failure with preserved ejection fraction in patients typically over 60 years old1,3,23,24

to standard HF therapies, ie, ACEi/ARBs and beta blockers7,13,25

between QRS voltage and left ventricular (LV) wall thickness26-28

of carpal tunnel syndrome1,12,13,16,29 or lumbar spinal stenosis21,22,30

showing increased LV wall thickness3,12,26,31,32

—autonomic nervous system dysfunction, including gastrointestinal complaints or unexplained weight loss3,12,18,33

Suspect The Signs Of ATTR-CM

ACEi,angiotensin-convertingenzymeinhibitors;ARBs,angiotensinreceptorblockers.

SUSPECT ATTR-CM

ATTR-CMisanunderdiagnosedcauseofheartfailure,particularlyheartfailurewithpreservedejectionfraction(HFpEF)inolderadults.23

CONSIDER THE FOLLOWING CLINICAL CLUES, ESPECIALLY IN COMBINATION, TO RAISE SUSPICION FOR ATTR-CM AND THE NEED FOR FURTHER TESTING

CLUES THAT MAY RAISE SUSPICION OF CARDIAC AMYLOIDOSIS

HFpEF: heart failure with preserved ejection fraction in patients typically over 60• InATTR-CM,diastolicfunctionisimpairedduetoamyloidfibrildepositioninthemyocardiumresultinginthickerandinelasticventriclestherebydecreasingthestrokevolume.ItisnotuntilthelaterstagesofATTR-CMdiseasethatejectionfractiondrops34,35

• Imagingclues,suchasreducedlongitudinalstrainwithapicalsparing,mayhelpincreasesuspicion7,36

INTOLERANCE to standard HF therapies, ie, ACEi/ARBs and beta blockers• Patientscandevelopadecreaseinstrokevolume,whichcanleadtolowbloodpressure.Asaresult,theycandevelopanintolerancetobloodpressure–loweringtherapies13,25

DISCORDANCE between QRS voltage and LV wall thickness• TheclassicECGfeatureofATTR-CMisadiscordancebetweenQRSvoltagetoLVmassratio7,15,28

DIAGNOSIS of carpal tunnel syndrome or lumbar spinal stenosis• CarpaltunnelsyndromeandlumbarspinalstenosisareoftenseeninATTR-CMduetoamyloiddepositionintheseareas1,13,21,22,29,30,37

• CarpaltunnelsyndromeinATTR-CMoftenprecedescardiacmanifestationsbyseveralyears2,16,38

ECHOCARDIOGRAPHY showing increased LV wall thickness• Increasedwallthicknesswithoutaclearexplanation(eg,hypertension)shouldraisesuspicionforcardiacamyloidosis7,12

• ExtracellularamyloiddepositionresultsinanincreasedLVwallthicknessthattendstobegreaterinATTR-CMthaninALcardiacamyloidosis,withreportedthicknessesforATTR-CMoftenbeingover15mm12,26,28,32

NERVOUS SYSTEM—autonomic nervous system dysfunction, including gastrointestinal complaints or unexplained weight loss• Gastrointestinalcomplaintsduetoautonomicdysfunctionincludediarrheaandconstipation11

• Orthostatichypotensionduetoautonomicdysfunctionisanothersymptomthatmayoccurwith ATTR-CM1-4,12

54

TOOLS FOR DIAGNOSIS IF YOU SUSPECT ATTR-CM

Detect ATTR-CM Utilizing PYP Nuclear Scintigraphy

PYP CARDIAC IMAGING (NUCLEAR SCINTIGRAPHY)• Anoninvasive,widelyavailablediagnostictoolwithhighsensitivityandspecificityforATTR-CM

• BothPlanarandSPECTimagingshouldbereviewedandinterpretedusingvisualandquantitativeapproaches–SPECTimagingisnecessaryforstudiesthatshowplanar myocardialuptakebecausetheycanhelpdifferentiate myocardialuptakefrombloodpooloroverlyingboneuptake

• Uses99mtechnetium-pyrophosphate(99mTc-PYP),aradioactivetracerutilizedasanadjunctinthediagnosisofATTR-CM,thoughnotFDAapprovedforthatuse

• Amulticenterinternationalstudyofscintigraphyatamyloidcentersofexcellencedemonstrated100%specificityforATTR-CMusingvisualgrade2or3withconcurrenttestingtoruleoutAL

• AmericanSocietyofNuclearCardiology(ASNC)PracticePointshighlighttheimportanceofPYPcardiacimagingindiagnosingATTR-CMnoninvasivelyandtherebyguidepatientmanagement

• Ifclinicalsuspicionremainshighforcardiacamyloidosisinspiteofanegativeorinconclusive99mTc-PYPscan,biopsyshouldbeconsidered

ENDOMYOCARDIAL BIOPSY (EMB)• RequireshistologywithCongoredstainingwithapple-greenbirefringencetodiagnosecardiacamyloidosis7,8

• Todetermineamyloidtype,immunohistochemistrytestingand/ormassspectrometryshould beperformed7

• Patientsmayexperiencediagnosticdelayforanumberofreasons,includingriskofcomplicationsandtheneedforspecializedcentersandexpertise7,8

GENETIC TESTING IS USED TO DETERMINE IF THE DISEASE IS HEREDITARY DUE TO A MUTATION IN THE TTR GENE. GENETIC COUNSELING AND GENE SEQUENCING ARE RECOMMENDED FOLLOWING THE CONFIRMATION OF ATTR-CM.4

DETECT TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM)

PYP,pyrophosphate.*Pleaseconsultindividuallabelingforrisks.

ADVANCED IMAGING TECHNIQUES TO HELP RAISE SUSPICION

ALTHOUGH THESE TECHNIQUES CANNOT DIAGNOSE ATTR-CM,39 ABNORMAL FINDINGS SHOULD PROMPT FURTHER TESTING TO ESTABLISH A DIAGNOSIS OF ATTR-CM. NONINVASIVE IMAGING TECHNIQUES INCLUDE:

•Advancedechocardiographywithspeckletrackingstrainimaging7,36,37,40–Relativeapicalsparingofgloballongitudinalstrain7

–“Icecreamconewithacherryontop”sign7

•CMR,withlategadoliniumenhancement,anddistinctT1mapping7,36,40–Increasedextracellularvolume,ECV7

ReprintedfromSiddiqiOK,RubergFL,Cardiacamyloidosis:anupdateonpathophysiology,diagnosis,andtreatment.TrendsCardiovascMed.28/1,10-21,2018,withpermissionfromElsevier.35

ReprintedbypermissionfromFontanaM,ChungR,HawkinsPN,MoonJC.Springer:HeartFailureReviews,Cardiovascularmagneticresonanceforamyloidosis.2015;20(2):133-144.

CMR,cardiacmagneticresonanceimaging;ECV,extracellularvolume;LGE,lategadoliniumenhancement.

Pre-contrast T1 LGE ECV5

76

TOOLS FOR DIAGNOSIS IF YOU SUSPECT ATTR-CM

Detect ATTR-CM Utilizing PYP Nuclear Scintigraphy

†AmericanSocietyofNuclearCardiology(ASNC).ASNCPracticePoints:99mtechnetium-pyrophosphateimagingfortransthyretincardiacamyloidosis.Availableat:https://www.asnc.org/files/19110%20ASNC%20Amyloid%20Practice%20Points%20WEB(2).pdf.

GRADING SYSTEM

SEMI-QUANTITATIVE VISUAL GRADING OF MYOCARDIAL 99MTC-PYP UPTAKE BY COMPARISON TO BONE (RIB) UPTAKE41†

Grade 0 No uptake and normal rib uptake

Grade 1

Grade 2

Grade 3

Uptake less than rib uptake

Uptake equal to rib uptake

Uptake greater than rib uptake with mild/absent rib uptake

GRADE MYOCARDIAL 99MTC-PYP UPTAKE41

GRADE0 GRADE1 GRADE2 GRADE3

USING NUCLEAR SCINTIGRAPHY TO HELP SUPPORT DIAGNOSIS OF ATTR-CM2

• AlandmarkstudysuggeststhatareliablediagnosisofATTR-CMcanbemadewithnuclearscintigraphyintheabsenceofhistologywhenallofthefollowingcriteriaaremet8: Thepatienthasheartfailurewithevidenceofcardiacamyloidosisviaechocardiography

orcardiacmagneticresonanceNuclearscintigraphyresultsfallwithintheparametersofthegradingsystem(ie,grade2or3)Immunoglobulinlightchainamyloidosis(AL)cardiacamyloidosishasbeenruledoutviabloodandurinetests

• Histologicalconfirmationandtypingviabiopsyshouldbepursuedincasesofsuspectedcardiacamyloidosiswhenthesecriteriaarenotsatisfied

• IfapatientispositiveforATTR-CMwithnuclearscintigraphy,genotypingisrecommendedtodetermineifit’swtATTRorhATTR8*

QUANTIFYING MYOCARDIAL PYP UPTAKE

Inclinicalpractice,bothasemi-quantitativevisualscoringandquantitativeapproachareapplied8:

1.Semi-quantitative:visualcomparisontoboneuptakeat3hours–Cardiacuptakeof99mTc-PYPevaluatedusingavisualscoringmethodinrelationtoboneuptake

(appliesagradingsystem)

2.Quantitative:myocardialtocontralaterallungratioofuptakeat1hour

NUCLEAR SCINTIGRAPHY

Bothplanarandsingle-photonemissioncomputedtomography(SPECT)imagingshouldbereviewedandinterpretedusingvisualandquantitativeapproaches.SPECTimagingisnecessaryforstudiesthatshowplanarmyocardialuptakebecauseitcanhelpdifferentiatemyocardialuptakefrombloodpooloroverlyingboneuptake.

*AlsoknownasvariantATTR.14

hATTR,hereditaryATTR;wtATTR,wild-typeATTR,previouslyknownassenilecardiacamyloidosis,senilesystemicamyloidosis,orage-relatedamyloidosis.

98

TOOLS FOR DIAGNOSIS IF YOU SUSPECT ATTR-CM

Detect ATTR-CM Utilizing PYP Nuclear Scintigraphy

Diagnostic CounselingPatient-centered counseling on diagnostic process

Biopsy

Congo Red Positive

Congo Red Negative

99mTc-PYP Scan§

Testing for AL Cardiac AmyloidosisPresence of monoclonal protein by free light chain assay and serum/urine immunofixation?

Heightened Clinical Suspicion for Cardiac AmyloidOlder adult with clinical, imaging, or biomarker evidence suggestive of cardiac amyloidosis

Yes No

Tissue Typing Immunohistochemistry & Mass Spectrometry(AL vs TTR vs Other)

Unlikely AL Cardiac

Amyloidosis

Negative Positive

hATTR¶ wtATTR

Unlikely ATTR Cardiac

Amyloidosis||

ATTR Cardiac Amyloidosis

TTR Genotyping

A POTENTIAL PATHWAY TO DIAGNOSIS13‡

A DIAGNOSTIC ALGORITHM FOR PATIENTS SUSPECTED WITH ATTR-CM

ReprintedfromBrunjesDL,CastanoA,ClemonsA,RubinJ,MaurerMS.TransthyretincardiacamyloidosisinolderAmericans.J Card Fail.2016;22(12):996-1003withpermissionfromElsevier.

AL,immunoglobulinlightchainamyloidosis;ATTR,transthyretinamyloidosis;hATTR,hereditaryATTR;wtATTR,wild-typeATTR,previouslyknownassenilecardiacamyloidosis,senilesystemicamyloidosis,orage-relatedamyloidosis.‡DiagnosticalgorithmdevisedbyBrunjesDL,etal.13

§Bothplanarandsingle-photonemissioncomputedtomography(SPECT)imagingshouldbereviewedandinterpretedusingvisualandquantitativeapproaches.SPECTimagingisnecessaryforstudiesthatshowplanarmyocardialuptakebecauseitcanhelpdifferentiatemyocardialuptakefrombloodpooloroverlyingboneuptake.

||Ifclinicalsuspicionremainshighforcardiacamyloidosisinspiteofanegative99mTc-PYPscan,biopsymaybeconsideredtoevaluateforothertypesofinfiltrativecardiomyopathy(eg,AA).

¶AlsoknownasvariantATTR.14

Gillmore,etal(2016)conductedastudytodeterminethediagnosticvalueofbonescintigraphyinATTR-CMpatients.Atotalof1217patientswereevaluatedofwhom857patientswithhistologicallyprovenamyloid(374withendomyocardialbiopsiesand360patientssubsequentlyconfirmedtohavenonamyloidcardiomyopathies)myocardialradiotraceruptakeonbonescintigraphywas>99%sensitiveand86%specificforcardiacATTRamyloid.FalsepositiveswerealmostexclusivelyfoundfromuptakeinpatientswithcardiacALamyloidosis.TheauthorsconcludedthatbonescintigraphyenablesthediagnosisofcardiacATTRamyloidosistobemadewithouttheneedfortissuebiopsyinpatientswhodonothaveamonoclonalgammopathy.Repeatinformation:withinthestudy,severalanalyseswereconductedandincludedidentificationofATTR-CMwith100%specificitywithscintigraphyvisualgrade2or3andconcurrentruleoutofAL.8*†

STUDY DESIGN

*RuleoutAL:testingforpresenceofmonoclonalproteinviaserumandurineimmunofixation.†SerumFreelightchainassay.

1110

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