a life-threatening disease that can go undetected
TRANSCRIPT
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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