Muller, Steven ASteven AMullerPeiró-Aventin, BelénBelénPeiró-AventinBiagioni, GiuliaGiuliaBiagioniTini, GiacomoGiacomoTiniSaturi, GiuliaGiuliaSaturiKronberger, ChristinaChristinaKronbergerAchten, AnoukAnoukAchtenDobner, StephanStephanDobnerTe Rijdt, Wouter PWouter PTe RijdtGasperetti, AlessioAlessioGasperettiTe Riele, Anneline S J MAnneline S J MTe RieleVarrà, Guerino GGuerino GVarràPonziani, AlbertoAlbertoPonzianiHirsch, AlexanderAlexanderHirschPorcari, AldostefanoAldostefanoPorcarivan der Meer, Manon GManon Gvan der MeerZampieri, MattiaMattiaZampierivan der Harst, PimPimvan der HarstKammerlander, AndreasAndreasKammerlanderBiagini, ElenaElenaBiaginivan Tintelen, J PeterJ Petervan TintelenBarbato, EmanueleEmanueleBarbatoAsselbergs, Folkert WFolkert WAsselbergsMenale, SilviaSilviaMenaleGräni, ChristophChristophGräniMerlo, MarcoMarcoMerloMichels, MichelleMichelleMichelsKnackstedt, ChristianChristianKnackstedtNitsche, ChristianChristianNitscheLonghi, SimoneSimoneLonghiMusumeci, BeatriceBeatriceMusumeciCappelli, FrancescoFrancescoCappelliGarcia-Pavia, PabloPabloGarcia-PaviaOerlemans, Marish I F JMarish I F JOerlemans2024-10-262024-10-262024-09https://boris-portal.unibe.ch/handle/20.500.12422/178239AIMS The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement. METHODS AND RESULTS We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%. CONCLUSIONS Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common.enATTRv Amyloidosis Cascade screening Repeat evaluation600 - Technology::610 - Medicine & healtharticle10.48350/1979173888786110.1002/ejhf.3339