# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=de-DE - IsLinearized=false - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Author=Belén Peiró-Aventín - CreationDate=D:20260427143140+05'30' - Creator=Adobe InDesign 15.1 (Windows) - ModDate=D:20260427180446+05'30' - Producer=Adobe PDF Library 15.0 - Subject=DOI: 10.1161/CIRCULATIONAHA.125.077833 Circulation, Volume. 153, Issue. 18, BACKGROUND: With the increasing diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) at earlier stages and new therapies, there is a rising demand for tools to stratify risk and prognosis. We evaluated the prognostic value of multiple circulating biomarkers for predicting outcomes in ATTR-CM. METHODS: We evaluated 12 different circulating biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI], mid-regional pro-adrenomedullin [MR-proADM], carbohydrate antigen 125 [CA125], soluble suppression of tumorigenicity 2 [sST2], cluster of differentiation antigen 146 [CD146], growth/differentiation factor-15 [GDF-15], alpha-klotho, fibroblast growth factor 23 [FGF-23], galectin-3, insulin-like growth factor-binding protein 7 [IGFBP-7], and estimated glomerular filtration rate [eGFR]) in 337 ATTR-CM patients from Spain. Cox models were employed to determine their predictive abilities. Findings were validated in 2 independent external cohorts of 210 patients from the United States and 416 patients from the ATTR-ACT trial, respectively. RESULTS: Over a median follow-up of 19.7 months (IQR, 6.5–42.3), 67 patients (19.9%) died/underwent heart transplantation, and 81 (24%) had heart failure events. MR-proADM was the biomarker with the strongest prognostic performance, with a C-index of 0.788 (95% CI, 0.723–0.851) for all-cause mortality and 0.721 (95% CI, 0.669–0.772) for the composite end point of death and heart failure events. MR-proADM was associated with multiple parameters of ATTR-CM severity and was independently associated with mortality, heart failure events, and the composite end point. MR-proADM ≥1.1 nmol/L was identified as the optimal prognostic threshold, and it improved prediction of mortality when added to the National Amyloid Center (area under the curve [AUC], 0.682 versus 0.737; P<0.001), Mayo (AUC, 0.659 versus 0.749; P<0.001), and the Columbia staging systems (AUC, 0.699 versus 0.768; P<0.001). In both validation cohorts, patients with MR-proADM ≥1.1 nmol/L had worse outcomes (P<0.001). This association was also confirmed in patients receiving tafamidis. CONCLUSIONS: In patients with ATTR-CM, MR-proADM levels are associated with disease severity and worse prognosis. MR-proADM improves prediction of all-cause mortality and captures heart failure events. - Title=MR-proADM Predicts Mortality and Heart Failure Events in ATTR Cardiac Amyloidosis - Trapped=False - dc:format=application/pdf - dc:title=MR-proADM Predicts Mortality and Heart Failure Events in ATTR Cardiac Amyloidosis - dc:creator=Belén Peiró-Aventín,Elena Revuelta-Lopez,Mariana Brandão,Julio Nuñez,Manuel A. Fernández-Rojo,Rosa M. Carmona,Borja Montejo,Alejandro Ferrando-Muñoz,Aránzazu Martín-García,Esther Gonzalez-Lopez,Fernando Dominguez,Andrea Camblor,María Ruiz-Cueto,Josep Lupon,Sergio Teruya,Dimitrios Bampatsias,Israt Jahan,Ana Royuela,Ahmad Masri,Mathew S. Maurer,Antoni Bayes-Genis,Pablo García-Pavía - dc:subject=biomarkers ◼,MR-proADM ◼,prognosis ◼,transthyretin - dc:description=DOI: 10.1161/CIRCULATIONAHA.125.077833 Circulation, Volume. 153, Issue. 18, BACKGROUND: With the increasing diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) at earlier stages and new therapies, there is a rising demand for tools to stratify risk and prognosis. We evaluated the prognostic value of multiple circulating biomarkers for predicting outcomes in ATTR-CM. METHODS: We evaluated 12 different circulating biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI], mid-regional pro-adrenomedullin [MR-proADM], carbohydrate antigen 125 [CA125], soluble suppression of tumorigenicity 2 [sST2], cluster of differentiation antigen 146 [CD146], growth/differentiation factor-15 [GDF-15], alpha-klotho, fibroblast growth factor 23 [FGF-23], galectin-3, insulin-like growth factor-binding protein 7 [IGFBP-7], and estimated glomerular filtration rate [eGFR]) in 337 ATTR-CM patients from Spain. Cox models were employed to determine their predictive abilities. Findings were validated in 2 independent external cohorts of 210 patients from the United States and 416 patients from the ATTR-ACT trial, respectively. RESULTS: Over a median follow-up of 19.7 months (IQR, 6.5–42.3), 67 patients (19.9%) died/underwent heart transplantation, and 81 (24%) had heart failure events. MR-proADM was the biomarker with the strongest prognostic performance, with a C-index of 0.788 (95% CI, 0.723–0.851) for all-cause mortality and 0.721 (95% CI, 0.669–0.772) for the composite end point of death and heart failure events. MR-proADM was associated with multiple parameters of ATTR-CM severity and was independently associated with mortality, heart failure events, and the composite end point. MR-proADM ≥1.1 nmol/L was identified as the optimal prognostic threshold, and it improved prediction of mortality when added to the National Amyloid Center (area under the curve [AUC], 0.682 versus 0.737; P<0.001), Mayo (AUC, 0.659 versus 0.749; P<0.001), and the Columbia staging systems (AUC, 0.699 versus 0.768; P<0.001). In both validation cohorts, patients with MR-proADM ≥1.1 nmol/L had worse outcomes (P<0.001). This association was also confirmed in patients receiving tafamidis. CONCLUSIONS: In patients with ATTR-CM, MR-proADM levels are associated with disease severity and worse prognosis. MR-proADM improves prediction of all-cause mortality and captures heart failure events. - dc:rights=© 2026 The Authors. - xmp:createdate=2026-04-27T14:31:40+05:30 - xmp:creatortool=Adobe InDesign 15.1 (Windows) - xmp:modifydate=2026-04-27T18:04:46+05:30 - xmp:metadatadate=2026-04-27T18:04:46+05:30 - xmpmm:instanceid=uuid:140ef017-214a-48d8-9c30-e8211ab4fdd5 - xmpmm:originaldocumentid=xmp.did:DE4D607E8A24681180838231FB1F3433 - xmpmm:documentid=xmp.id:c872fecd-fed9-724b-ae3d-49cda970a46f - xmpmm:renditionclass=proof:pdf - xmpmm:versionid=1 - xmpmm:derivedfrom=xmp.iid:a5ebdf23-e3eb-f34a-b90a-250b37602188xmp.did:99f5b2a2-4907-8445-80fb-51fc63823cc0default - xmpmm:history=convertedfrom application/x-indesign to application/pdfAdobe InDesign 15.1 (Windows)2026-04-27T14:31:40+05:30converteduuid:7fd008b0-4dad-4e8e-8ca4-ea14ac82de64converted to PDF/A-3aPreflight2026-04-27T18:04:46+05:30 - xmprights:marked=True - pdf:producer=Adobe PDF Library 15.0 - pdf:trapped=False - pdfuaid:part=1 - pdfaid:part=3 - pdfaid:conformance=A - pdfaextension:schemas=http://ns.adobe.com/xap/1.0/mm/xmpMMXMP Media Management SchemainternalUUID based identifier for specific incarnation of a documentInstanceIDURIinternalThe common identifier for all versions and renditions of a document.OriginalDocumentIDURIhttp://ns.adobe.com/pdf/1.3/pdfAdobe PDF SchemainternalA name object indicating whether the document has been modified to include trapping informationTrappedTexthttp://www.aiim.org/pdfa/ns/id/pdfaidPDF/A ID SchemainternalPart of PDF/A standardpartIntegerinternalAmendment of PDF/A standardamdTextinternalConformance level of PDF/A standardconformanceTexthttp://www.aiim.org/pdfua/ns/id/pdfuaidPDF/UA ID SchemainternalPart of PDF/UA standardpartInteger ## Contents ### Page 1 ORIGINAL RESEARCH ARTICLE # MR-proADM Predicts Mortality and Heart FailureEvents in ATTR Cardiac Amyloidosis Belén Peiró-Aventín[ ![Equation 1]() ](https://orcid.org/0000-0001-9081-7003) , MD; Elena Revuelta-Lopez[ ![Equation 1]() ](https://orcid.org/0000-0001-8962-5936) , PhD; Mariana Brandão[ ![Equation 1]() ](https://orcid.org/0000-0001-9913-0435) , MD; Julio Nuñez[ ![Equation 1]() ](https://orcid.org/0000-0003-1672-7119) , MD, PhD;Manuel A. Fernández-Rojo[ ![Equation 1]() ](https://orcid.org/0000-0002-2240-1951) , PhD; Rosa M. Carmona, MLT; Borja Montejo[ ![Equation 1]() ](https://orcid.org/0009-0000-4837-5109) , MLT; Alejandro Ferrando-Muñoz, BS;Aránzazu Martín-García, PhD; Esther Gonzalez-Lopez[ ![Equation 1]() ](https://orcid.org/0000-0003-4175-1487) , MD, PhD; Fernando Dominguez[ ![Equation 1]() ](https://orcid.org/0000-0001-8408-363X) , MD, PhD; Andrea Camblor[ ![Equation 1]() ](https://orcid.org/0009-0005-0592-598X) , MD;María Ruiz-Cueto[ ![Equation 1]() ](https://orcid.org/0009-0002-7835-3722) , MD; Josep Lupon, MD; Sergio Teruya[ ![Equation 1]() ](https://orcid.org/0000-0002-4653-9330) , MD; Dimitrios Bampatsias, MD; Israt Jahan[ ![Equation 1]() ](https://orcid.org/0000-0003-0948-8439) , MD;Ana Royuela[ ![Equation 1]() ](https://orcid.org/0000-0003-1665-081X) , PhD; Ahmad Masri[ ![Equation 1]() ](https://orcid.org/0000-0002-6390-6526) , MD; Mathew S. Maurer[ ![Equation 1]() ](https://orcid.org/0000-0001-5400-5008) , MD; Antoni Bayes-Genis[ ![Equation 1]() ](https://orcid.org/0000-0002-3044-197X) , MD, PhD;Pablo García-Pavía[ ![Equation 1]() ](https://orcid.org/0000-0002-5470-2257) , MD, PhD Correspondence to: Pablo García-Pavía, MD, PhD, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla, 2, 28222 Madrid, Spain, Email; or Antoni Bayes-Genis, MD, PhD, Heart Institute, Hospital Universitari Germans Trias i Pujol, UAB, Carretera del Canyet s/n, 08916 Badalona,Spain, Email Supplemental Material is available at. © 2026 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under theterms of the License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. BACKGROUND: With the increasing diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) at earlier stages and newtherapies, there is a rising demand for tools to stratify risk and prognosis. We evaluated the prognostic value of multiplecirculating biomarkers for predicting outcomes in ATTR-CM. METHODS: We evaluated 12 different circulating biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI], mid-regional pro-adrenomedullin [MR-proADM], carbohydrate antigen 125 [CA125], solublesuppression of tumorigenicity 2 [sST2], cluster of differentiation antigen 146 [CD146], growth/differentiation factor-15[GDF-15], alpha-klotho, fibroblast growth factor 23 [FGF-23], galectin-3, insulin-like growth factor-binding protein7 [IGFBP-7], and estimated glomerular filtration rate [eGFR]) in 337 ATTR-CM patients from Spain. Cox models wereemployed to determine their predictive abilities. Findings were validated in 2 independent external cohorts of 210 patientsfrom the United States and 416 patients from the ATTR-ACT trial, respectively. RESULTS: Over a median follow-up of 19.7 months (IQR, 6.5–42.3), 67 patients (19.9%) died/underwent heart transplantation,and 81 (24%) had heart failure events. MR-proADM was the biomarker with the strongest prognostic performance, with aC-index of 0.788 (95% CI, 0.723–0.851) for all-cause mortality and 0.721 (95% CI, 0.669–0.772) for the composite endpoint of death and heart failure events. MR-proADM was associated with multiple parameters of ATTR-CM severity and wasindependently associated with mortality, heart failure events, and the composite end point. MR-proADM ≥1.1 nmol/L wasidentified as the optimal prognostic threshold, and it improved prediction of mortality when added to the National AmyloidCenter (area under the curve [AUC], 0.682 versus 0.737; P<0.001), Mayo (AUC, 0.659 versus 0.749; P<0.001), and theColumbia staging systems (AUC, 0.699 versus 0.768; P<0.001). In both validation cohorts, patients with MR-proADM ≥1.1nmol/L had worse outcomes (P<0.001). This association was also confirmed in patients receiving tafamidis. CONCLUSIONS: In patients with ATTR-CM, MR-proADM levels are associated with disease severity and worse prognosis. MR-proADM improves prediction of all-cause mortality and captures heart failure events. Key Words: biomarkers ◼ MR-proADM ◼ prognosis ◼ transthyretin Transthyretin amyloid cardiomyopathy (ATTR-CM)is a progressive condition produced by the depo-sition of misfolded transthyretin (TTR) mono-mers, forming amyloid fibrils.1,2 This process leadsto the development of a restrictive cardiomyopathy,frequently associated with poor long-term progno-sis.3 The disease can stem from destabilizing variantsin the TTR gene (ATTRv) or can occur in individuals ### Page 2 with wild-type TTR in a process associated with aging(ATTRwt).2 ## Clinical Perspective ## What Is New? - • Circulating mid-regional pro-adrenomedullin (MR-proADM) is associated with markers of heart failureand disease severity in patients with transthyretinamyloid cardiomyopathy. - • Mid-regional pro-adrenomedullin predicts mortalityand heart failure events in transthyretin amyloid car-diomyopathy, even after adjustment for establishedprognostic factors such as NT-proBNP (N-terminalpro-B-type natriuretic peptide), estimated glomeru-lar filtration rate, diuretic dose, and New York HeartAssociation functional class. - • Mid-regional pro-adrenomedullin ≥1.1 nmol/L iden-tifies patients at high risk of events and improvesmortality prediction when added to the Mayo,National Amyloid Center, and Columbia stagingsystems. ## What Are the Clinical Implications? - • Incorporating mid-regional pro-adrenomedullin intoroutine clinical testing and established staging sys-tems could improve risk stratification and guideclinicians in selecting the most appropriate thera-peutic strategy in patients with transthyretin amy-loid cardiomyopathy. Nonstandard Abbreviations and Acronyms ADM adrenomedullin AF/AFL atrial fibrillation/atrial flutter ATTR-CM transthyretin amyloidcardiomyopathy ATTRv variant transthyretin amyloidosis ATTRwt wild-type transthyretin amyloidosis AUC area under the curve CA125 carbohydrate antigen 125 CD146 cluster of differentiation antigen146 CMR cardiac magnetic resonance DPD 3,3-diphosphono-1,2-propanodicarboxylic acid eGFR estimated glomerular filtration rate FGF23 fibroblast growth factor 23 GDF-15 growth/differentiation factor 15 GLS global longitudinal strain hsTnI high sensitivity troponin I IGFBP7 insulin-like growth factor bindingprotein 7 LVEF left ventricular ejection fraction MR-proADM mid-regional pro-adrenomedullin NAC National Amyloid Center NT-proBNP N-terminal pro-B-type natriureticpeptide NYHA New York Heart Association PASP pulmonary artery systolic pressure SPECT single photon emission computedtomography sST2 soluble suppression oftumorigenicity 2 TAPSE tricuspid annular plane systolicexcursion TTR transthyretin Over the past decade, significant advances have beenmade in understanding the disease. While its real preva-lence remains unknown, what was once considered arare condition, predominantly affecting elderly men andusually diagnosed at an advanced phase, is now increas-ingly identified at earlier stages because of advancesin noninvasive diagnosis and the availability of disease-modifying treatments.4 Moreover, ATTR-CM is now fre-quently recognized among patients with several commonclinical scenarios such as heart failure with preservedejection fraction, severe aortic stenosis, and hypertrophiccardiomyopathy.4–6 As more patients with ATTR-CM are diagnosed atearlier stages of the disease and have access to newspecific treatments, there is an increasing need for spe-cific tools to stratify their risk and prognosis accurately. Classic biomarkers such as N-terminal pro-B-typenatriuretic peptide (NT-proBNP), estimated glomerularfiltration rate (eGFR), and troponin are established pre-dictors of mortality in ATTR-CM patients, becoming keycomponents of current prognostic scores.7,8 However,these scores primarily focus on survival and were devel-oped years ago, when patients were frequently diag-nosed at advanced disease stages. With the increasinglife expectancy of ATTR-CM patients today, there is agrowing interest in assessing not only mortality but alsoin identifying individuals at risk of heart failure decom-pensation. Although there are no staging systems to pre-dict heart failure related events in ATTR-CM, heart failureepisodes are associated with worse prognosis9 and arefrequently included in the primary end points of the clini-cal trials assessing new drugs to treat this disease. Accordingly, we sought to evaluate the prognosticrole of 12 circulating biomarkers previously described inheart failure as predictors of all-cause mortality and heartfailure events in patients with ATTR-CM. ## METHODS The data that support the findings of this study are availablefrom the corresponding author upon reasonable request.Qualified researchers may submit a request containingthe research objectives, end points/outcomes of interest, ### Page 3 a statistical analysis plan, data requirements, a publicationplan, and qualifications of the researcher(s). Requests will bereviewed by corresponding authors. If approved, informationnecessary to address the research question will be providedunder the terms of a data sharing agreement. Requests may besubmitted to corresponding authors. ### Participants Consecutive patients diagnosed with ATTR-CM from HospitalUniversitario Puerta de Hierro Majadahonda (Madrid, Spain)and Hospital Universitari Germans Trias I Pujol (Badalona,Barcelona, Spain) who had a blood sample collected wereincluded. Baseline assessments were performed betweenDecember 2014 and October 2022, with the majority ofpatients (99.1%) enrolled from January 2017 onward. Thestudy was approved by the Hospital Universitario Puerta deHierro Majadahonda ethics committee and in agreement withthe principles of the Helsinki Declaration. Patients providedwritten consent for collection of samples. ATTR-CM was diagnosed invasively and noninvasively by:(1) demonstration of TTR amyloid deposits on endomyocardialbiopsy; (2) demonstration of TTR amyloid deposits on extracar-diac biopsy and echocardiographic or cardiac magnetic reso-nance (CMR) criteria (ie, diffuse subendocardial or transmurallate gadolinium enhancement with abnormal gadolinium kinet-ics); and (3) cardiac uptake grade 2 or 3 on 3,3-diphosphono-1,2-propanodicarboxylic acid single photon emission computedtomography (DPD SPECT) scintigraphy and no evidence ofmonoclonal protein (negative serum and urine immunofixationand negative serum free light chains) in the presence of echo-cardiographic or CMR criteria for cardiac amyloidosis accord-ing to the European Society of Cardiology position paper ondiagnosis and treatment of cardiac amyloidosis.1 Both patientswith ATTRv and ATTRwt were enrolled. Results were validated in 2 independent external cohorts.The first validation cohort included 210 patients with ATTR-CMfrom 2 centers from the United States: Oregon Health andScience University Medical Center (Portland, OR), and ColumbiaUniversity Irving Medical Center (New York, NY). The sameinclusion criteria for the derivation cohort were applied. Thesecond validation cohort included 416 patients from the ATTR-ACT trial, a phase 3, multicenter, placebo-controlled, double-blind, randomized trial that evaluated the safety and efficacyof tafamidis in ATTR-CM.10 ATTR-ACT trial included ATTR-CMpatients with both hereditary and wild-type ATTR-CM; maininclusion criteria comprised an age between 18 and 90 years,New York Heart Association (NYHA) class I to III, and a base-line NT-proBNP ≥600 pg/mL. Participants were assigned in a2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis,or placebo, respectively. Out of the 441 subjects randomized inthe ATTR-ACT trial, 416 had a baseline blood sample availableand were included in this analysis. ### Baseline Clinical Characteristics Demographic and clinical data at baseline evaluation were col-lected from clinical records in the initial and the first validationcohort using a uniform methodology. Age, type of ATTR-CM,NYHA class, and medical therapy including ATTR specifictherapies were obtained. Presence of comorbidities such asischemic cardiomyopathy or previous stroke or atrial fibrillationwere also collected. Baseline characteristics included eGFR,calculated using the CKD-EPI (Chronic Kidney DiseaseEpidemiology Collaboration) formula, cardiac biomarkers, andechocardiographic parameters obtained at first evaluation.ECG findings were also collected. Torasemide doses wereconverted to furosemide equivalents, using a ratio of 20 mg oftorasemide to 40 mg of furosemide to standardize furosemidedosing. Baseline clinical characteristics of patients from ATTR-ACT were obtained from eCRF. ### Outcomes The study outcomes included all-cause mortality, worseningheart failure (defined as hospital admission for heart failureor ambulatory administration of intravenous diuretics to treatcongestive symptoms), and a composite end point of all-causemortality, worsening heart failure, or heart transplant. Eventswere collected by investigators blinded to biomarker levelsthrough a thorough review of medical records and by contactingpatients to evaluate their survival status. Outcomes of patientsfrom the ATTR-ACT cohort were captured from the study data-base. Patients were followed until death or last available clinicalcontact, with October 2023 being the last censoring date. Forsurvival analyses, follow-up was truncated at 3 years, such thatpatients with longer follow-up were censored at that time point. ### Biomarkers Carbohydrate antigen 125 (CA125), insulin-like growthfactor-binding protein 7 (IGFBP7), galectin-3, cluster ofdifferentiation antigen 146 (CD146), growth/differen-tiation factor-15 (GDF-15), alpha-klotho, soluble suppres-sion of tumorigenicity biomarker 2 (sST2), mid-regionalpro-adrenomedullin (MR-proADM) and fibroblast growthfactor 23 (FGF23) and high-sensitivity troponin I (hsTnI) lev-els were determined in a blinded manner at Centro NacionalInvestigaciones Cardiovasculares (CNIC; Madrid, Spain), atHospital Universitario Puerta de Hierro (Madrid, Spain) or atHospital Universitari Germans Trias I Pujol (Barcelona, Spain)by immunoassays in EDTA-plasma and serum/plasma sam-ples obtained from patients with ATTR-CM from the deriva-tion cohort. Additionally, NT-proBNP and eGFR were collectedfrom baseline evaluation at participating centers. Biomarkersexamined were selected based on their previous description asprognostic factors in cohorts of patients with heart failure andthe availability of commercial immunoassays.11,12 The analysismethod followed for each biomarker was according to the man-ual provided by the manufacturer. A more detailed descriptionof the methods used to measure each biomarker is available inthe. Subsequently, MR-proADM levels were measured in ablinded manner in plasma samples from patients from the 2validation cohorts following the same methodology as in thederivation cohort. ### Statistical Analysis Baseline continuous and categorical variables are presentedas median (interquartile range) and frequencies (percentage),respectively. Survival estimations were evaluated from the firstmedical contact to the last follow-up or death. Follow-up ofpatients enrolled in double-blind, placebo-controlled clinical ### Page 4 trials in the derivation and the first validation cohorts was cen-sored at the time of trial enrollment. Initially, a univariable Cox regression model was employedto assess the predictive performance of the 12 biomarkersfor all-cause mortality and the composite end point. The bio-marker with strongest predictive capacity was selected forfurther analysis. To evaluate the performance of MR-proADMover time, follow-up was censored at 3 years for all survival-time analyses. This time frame was selected based on previousstudies13 because of the reported median survival of patientswith ATTR-CM14 and because of the high rate of early eventsin these patients, making models less stable over extendedperiods. Subsequently, we evaluated MR-proADM according toclinical, ECG, and echocardiographic parameters to evaluateits association with markers of disease severity. Patients werestratified based on MR-proADM levels, using the establishedstandard cutoff. Characteristics and outcomes were comparedbetween groups using the Mann-Whitney U test for continuousvariables and the Pearson χ2 test for categorical variables. Given the potential nonlinear relationship between levelsof biomarkers and the risk of events, MR-proADM risk gradi-ent across all its values was assessed using fractional polyno-mial regression after univariable and multivariable approaches,with model selection based on Akaike and Bayesian informa-tion criteria. The best fitting model was a first-order fractionalpolynomial with a power of −1.0. The first multivariable modelincluded NT-proBNP and eGFR (variables included in the UKNational Amyloid Center [NAC] prognostic staging system7),whereas the second model incorporated NT-proBNP, eGFR,diuretic dose indexed by body weight, and NYHA functionalclass (variables included in the Columbia prognostic stagingsystem13). The optimal cutoff for MR-proADM was selected usingtime-dependent receiver operating curve analysis with nearest-neighbor estimation based on the method proposed by Heagerty,Lumley, and Pepe,15 with the cutoff selected using the Perkinsand Schisterman criterion (stroccurve instruction in STATA).16,17The cutoff was estimated using 1-year mortality, as this timeframe minimizes biomarker variability over longer follow-up peri-ods and provides a reliable association between MR-proADMlevels and outcomes. Kaplan-Meier curves were plotted for thecomposite end point and all-cause mortality. For worsening heartfailure, cumulative incidence curves were estimated using acompeting risk regression model based on the Fine and Graymethod,18 with death considered as the competing event. The incremental value of MR-proADM combined with theNAC and the Columbia staging systems was evaluated by com-paring the predictive performance of the survival models usingHarrell’s C-statistic and by assessing their areas under thecurve (AUC) for predicting 3-year mortality. We also evaluatedthe incremental value of MR-proADM to the Mayo staging sys-tem. Since troponin T was not available, hsTnI was determinedinstead. Accordingly, we applied the cutoff of 80 ng/L, pro-posed by De Michieli et al,19 hereafter referring to this approachas a modified Mayo staging system. Finally, the results were validated using 2 external validationcohorts. Although survival was assessed in all patients, worsen-ing heart failure events were not fully captured in a large pro-portion of patients from the first validation cohort (US cohort)because many individuals were primarily followed at localcenters. Therefore, this cohort was used exclusively to validatethe results for all-cause mortality. The second cohort (ATTR-ACT cohort), obtained from a clinical trial setting, provided dataon mortality and heart failure hospitalizations, allowing valida-tion of both all-cause mortality and the composite end point. All statistical tests were 2-sided. A value of P<0.05 wasconsidered statistically significant. Analyses were performedusing STATA (version 16; StataCorp). ## RESULTS ### Baseline Characteristics and Outcomes A total of 337 ATTR-CM patients comprised the initialcohort, 296 (87.8%) from Hospital Universitario Puertade Hierro and 41 (12.2%) from Hospital UniversitariGermans Trias I Pujol. The median time from definitiveATTR-CM diagnosis to blood sample collection was 62days (IQR, −27 to 263 days), and the median follow-uptime was 19.7 months (IQR, 6.5–42.3 months). The median age of the overall cohort was 78.3 years(73.1 to 82.9), 276 (81.9%) were men, 291 (86.35%)had ATTRwt, and 92 (27.3%) were receiving tafamidisat baseline or initiated it during the initial 12 monthsof follow-up. Among the 46 patients with ATTRv, themost common variant was Val142Ile (16 patients). Mostpatients were in NYHA class II (182 patients; 54%),whereas 92 (27.3%) were in NYHA I, and 63 (18.7%)were in NYHA III. Median eGFR was 61 mL/min (47–78mL/min) and NT-proBNP 2209 pg/mL (942–4140 pg/mL). Two thirds (228; 67.7%) of the patients were underdiuretic treatment, and the median furosemide dose was0.47 mg/kg (0–0.87 mg/kg). Additional baseline char-acteristics are presented in Table 1. According to the NAC staging system, 187 patients(55.5%) were classified as stage I, 98 (29.1%) as stageII, and 52 (15.4%) as stage III. Median survival by stagewas 74.5 months (95% CI, 74.4; could not be estimated)for stage I, 44.2 months (95% CI, 32.1; could not beestimated) for stage II, and 36.6 months (95% CI, 23.2;could not be estimated) for stage III. Throughout the follow-up period, 66 (19.6%) patientsdied, 81 (24%) experienced heart failure events, andone (0.3%) underwent heart transplant. A total of 80(23.7%) patients were censored because of inclusionin a double-blind, placebo-controlled clinical trial, with amedian follow-up time before enrollment in the clinicaltrial of 123 [91–203] days. The median survival time ofthe overall cohort was 6.2 years (95% CI, 5.5 years; couldnot be estimated). The estimated 1-year survival was93% (95% CI, 89.2–95.5), 3-year survival was 74.5%(95% CI, 67.5–80.2), and 5-year survival was 62.8%(95% CI, 53.9–70.5). Kaplan Meier curves for mortality,worsening heart failure, and the composite end point aredisplayed in from. As shown in Table 1, patients with events were morelikely to be in a more advanced NYHA class, have a ### Page 5 *All-cause death, worsening heart failure, or heart transplant. ATTR indicates transthyretin amyloidosis; eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; hsTnI, high-sensitivity troponinI; LA, left atrium; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP,pulmonary artery systolic pressure; and TAPSE, tricuspid annular plane systolic excursion. history of atrial fibrillation/flutter (AF/AFL), previousheart failure admissions, elevated NT-proBNP levels,and reduced eGFR values. They were more commonlytreated with diuretics and beta-blockers and presentedmore frequently with echocardiographic findings ofadvanced disease, such as lower tricuspid annular planesystolic excursion (TAPSE), higher lateral E/e’, pulmo-nary artery systolic pressures (PASPs), and global longi-tudinal strain (GLS). Pericardial effusion was also morefrequent in these patients. We performed site-stratified analyses comparingpatients from Hospital Universitario Puerta de HierroMajadahonda (N=296) and Hospital UniversitariGermans Trias i Pujol (N=41). Patients from Puerta deHierro were younger, more often men, and more fre-quently in advanced NYHA class, with a higher preva-lence of ATTRv and tafamidis use, as expected in anational referral center. Although minor echocardio-graphic and analytical differences were also noted, therewas no evidence that patients from either hospital weresystematically in a more advanced disease stage (). #### Prognostic Role of Circulating Biomarkers The prognostic performance of circulating biomark-ers was individually assessed in 2 regression models ### Page 6 to predict all-cause death and the composite end point.Harrell’s C-index values were calculated to assess thepredictive capacity of the biomarker (Table 2). MR-proADM demonstrated the strongest prognostic perfor-mance, with a C-index of 0.788 (95% CI, 0.723–0.851)for all-cause mortality and 0.721 (95% CI, 0.669–0.772)for the composite end point. Based on these results, MR-proADM was selected for further analysis. All estimates are derived from univariable Cox models. CA125 indicates carbohydrate antigen 125; CD146, cluster of differentiation antigen 146; eGFR, estimated glomerularfiltration rate; FGF23, fibroblast growth factor 23; GDF-15, growth/differentiation factor-15; hsTnI, high-sensitivity troponin I;IGFBP7, insulin-like growth factor-binding protein 7; MR-ProADM, mid-regional pro-adrenomedullin; NT-proBNP, N-terminalpro–B-type natriuretic peptide; and sST2, soluble suppression of tumorigenicity biomarker 2. #### Association of MR-proADM With Markers ofSeverity Median baseline level of MR-proADM was 0.816(0.617–1.12) nmol/L. A total of 174 patients (51.6%)had concentrations of MR-proADM >0.79 nmol/L, whichis the cutoff value proposed in chronic heart failure.20,21 Patients with MR-proADM measurements above thiscutoff value exhibited more frequently several markersof disease severity (Table 3). These included a moreadvanced NYHA functional class, history of AF, previousadmissions for heart failure, lower left ventricular ejec-tion fraction (LVEF), parameters of diastolic dysfunction,presence of pericardial effusion, elevated PASP andGLS, reduced TAPSE, and higher doses of loop diuretics.Moreover, patients with higher MR-proADM also exhib-ited higher NT-proBNP and lower eGFR. #### Association of MR-proADM Levels With Prognosis Patients with MR-proADM above the normal cutoff val-ues had higher mortality, more worsening heart failureevents and higher incidence of the composite end pointthan patients who had MR-proADM below this threshold(P<0.001 for all;). Gradient ofrisk of MR-proADM levels for predicting all-cause deathand the composite end point was evaluated using frac-tional polynomial regression. In univariable assessment,MR-proADM was statistically associated with mortalityand the composite end point (P<0.001). After multivari-able adjustment with NT-proBNP and eGFR (model 1)and with NT-proBNP, eGFR, NYHA and diuretic dose(model 2), MR-proADM persisted to be significantly as-sociated with all-cause mortality and the composite endpoint in both models (Figure 1). #### Optimal Cutoff of MR-proADM for ATTR-CM The optimal cutoff value of MR-proADM at 1 year in ourcohort was 1.1 nmol/L. Patients with MR-proADM lev-els above this threshold experienced worse outcomes(P<0.001 for all end points; Figure 2). Median survivalamong patients with MR-proADM <1.1 nmol/L was notreached (95% CI, 74.5 months; could not be estimated),compared with 29.4 months (95% CI, 21.2–37.5) in thosewith MR-proADM ≥1.1 nmol/L. Among patients with MR-proADM <1.1 nmol/L, 1-year and 3-year survival rateswere 96.9% (93.2–98.6%) and 87.6% (80.4–92.2%),respectively, compared with 82.8% (72.1–89.7%) and40.5% (26.9–53.8%) in those with MR-proADM ≥1.1nmol/L (P<0.001). Overall, 91 patients (27%) had MR-proADM levels>1.1 nmol/L. Baseline characteristics stratified by thisthreshold are summarized in. When stratifying by site, MR-proADM remainedstrongly associated with mortality in patients from theHospital Puerta de Hierro (P<0.001), whereas in thosefrom the Hospital Germans Trias i Pujol, the associa-tion did not reach statistical significance despite thedirection of the effect was consistent, likely explained ### Page 7 *All-cause death, worsening heart failure, and heart transplant. ATTR indicates transthyretin amyloidosis; eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain;hsTnI, high-sensitivity troponin I; LA, left atrium; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejec-tion fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; and TAPSE, tricuspid annularplane systolic excursion. by the low number of patients included from this center(). #### Additive Value to Current Staging Systems In our cohort, the NAC staging system achieved an AUCof 0.682 (95% CI, 0.604–0.760) for predicting 3-yearmortality. The addition of MR-proADM, dichotomizedwith a cutoff of 1.1 nmol/L, enhanced the AUC to 0.737(95% CI, 0.661–0.813; Figure 3A). Additionally, Har-rell’s C-index significantly improved with the inclusionof MR-proADM from 0.694 (95% CI, 0.624–0.765) forthe NAC model alone to 0.765 (95% CI, 0.691–0.838)when combined with MR-proADM, with a P value for thedifference of 0.005 (Table 4). ### Page 8 ![Figure 1]() ![Figure 2]() The modified Mayo staging system yielded an AUC of0.659 (95% CI, 0.572–0.746), improving to 0.749 (95%CI, 0.659–0.83) after addition of MR-proADM (Fig-ure 3B). Similarly, Harrell’s C-index increased from 0.702(95% CI, 0.627–0.777) to 0.790 (95% CI, 0.722–0.857;P=0.011; Table 4). Finally, the Columbia staging system achieved anAUC of 0.699 (95% CI, 0.632–0.766), and incorpora-tion of MR-proADM improved the AUC to 0.768 (95%CI, 0.702–0.833; Figure 3B). This improvement wasalso reflected in Harrell’s C-index, which increasedfrom 0.702 (95% CI, 0.650–0.754) to 0.806 (95% CI,0.749–0.864), with a P value for the difference <0.001(Table 4). #### External Validation The first external validation cohort consisted of 210US patients with ATTR-CM (median age of 77.8 years[73.55–82.26 years]), of whom 90.5% were men, 81.9%had ATTRwt, and 60% were on tafamidis treatment ### Page 9 *The modified Mayo staging system includes NT-proBNP ≤ or >3000 pg/mLand hsTnI ≤ or >80 ng/L. †The NAC staging system includes NT-proBNP ≤ or >3000 pg/mL and eGFR≤ or >45 mL/min/m2. ‡The Columbia staging system includes NT-proBNP ≤ or >3000 pg/mL andeGFR ≤ or >45 mL/min/m2. NYHA functional class (I-IV) and diuretic dose in-dexed by weight (0, >0 to 0.5, >0.5 to 1, and >1 mg/kg). eGFR indicates estimated glomerular filtration rate; hsTnI, high-sensitivity tro-ponin I; MR-proADM, mid-regional pro-adrenomedullin; NAC, National AmyloidCenter; NT-proBNP, N-terminal pro–B-type natriuretic peptide; and NYHA, NewYork Heart Association . ![Figure 3]() (). Patients in this cohort exhibited a more ad-vanced NYHA functional class and had been previouslyadmitted for heart failure more frequently than in thederivation cohort. Patients showed slightly lower eGFRand LVEF values and were treated with tafamidis morefrequently (60% versus 25.5%; P<0.001), reflecting theearlier availability of tafamidis in the United States com-pared with Spain. All other baseline characteristics wereconsistent between the 2 cohorts. Over a median follow-up of 22.8 months (IQR, 7.9–48.4), there were 70 deaths (33.3%) and 5 heart trans-plants (2.4%). Consistent with the derivation cohort,MR-proADM demonstrated a good predictive perfor-mance for the end point of all-cause mortality, with aHarrell’s C-index of 0.725 (95% CI, 0.646–0.805).Patients with MR-proADM <1.1 nmol/L did not reachmedian survival, with a 1-year survival of 97% (91–99%)and 3-year survival of 88.5% (79.6–93.6%). In contrast,patients with MR-proADM ≥1.1 nmol/L had a mediansurvival of 27 months (95% CI, 19.1; could not be esti-mated), with a 1-year survival of 75% (64–84%) and a3-year survival of 39.2% (27.9–50.2%; Figure 4A). These findings were subsequently validated in a sec-ond validation cohort of 416 patients from the ATTR-ACT trial. Participants exhibited a median age of 75years (71–79); 90.6% were men, 76.9% had wild-typeATTR, and 59.9% were receiving tafamidis ().Compared with the derivation cohort, this group had amore advanced NYHA class, higher NT-proBNP lev-els, lower eGFR and LVEF, and a greater proportion ofpatients were receiving diuretic therapy. These charac-teristics likely reflect a more advanced disease stage andare consistent with the earlier recruitment period of thiscohort (2013 to 2015). Over a follow-up period of 30 months, 136 patientsdied (32.7%), 171 (41.1%) were hospitalized for heartfailure, 11 (2.6%) underwent heart transplantation, and 3(0.72%) received a left ventricular assist device. Patients with MR-proADM levels ≥1.1 nmol/L exhib-ited a significantly higher incidence of mortality and thecomposite outcome of mortality and heart failure hos-pitalization (Figure 4B and 4C). Findings remained con-sistent in the subgroup of patients receiving tafamidis(). ## DISCUSSION This study is the first to systematically evaluate multiplecirculating biomarkers related to heart failure in ATTR-CM. Our findings highlight the potential of using MR-proADM to assess prognosis in ATTR-CM, a conditionwith a unique pathophysiology that differs from otherforms of heart failure. Our work shows that increasedMR-proADM levels are associated with several markersof severity of the disease and are independently associ-ated with all-cause death and heart failure events. More-over, we identified a specific cutoff value for MR-proADM ### Page 10 ![Figure 4]() that accurately identified patients with poorer outcomesindependently of currently established prognostic bio-markers like NT-proBNP and eGFR. Lastly, we confirmedthe incremental value of MR-proADM when added to theNAC, Mayo, and Columbia prognostic staging systemsand validated the prognostic capacity of the proposedMR-proADM cutoff in 2 external cohorts. The landscape of amyloidosis has undergone out-standing changes in recent years.1,2 With the advancesin noninvasive diagnosis and the development of spe-cific treatments, a growing number of patients are beingdiagnosed at earlier stages of the disease, and the prog-nosis has significantly improved.22,23 Consequently, thereis a pressing need for tools to accurately stratify therisk of these patients, identifying those requiring closermonitoring and those likely to benefit the most from tar-geted treatments including the possibility of aggressiveapproaches combining several specific therapies. The first significant contribution to predict prognosisin ATTR-CM was made in 2016 by Grogan et al, whodemonstrated that NT-proBNP and troponin T wereindependent predictors of mortality in ATTRwt, andcreated the first staging system based on the valuesof both biomarkers.8 In 2018, Gillmore et al proposedand validated the NAC staging system, based on NT-proBNP and eGFR levels, that predicted survival in bothATTRwt and ATTRv patients.7 This staging system hassince gained recognition and is widely used in clinicalpractice and clinical trials. Building upon this foundation,Cheng et al identified weight-indexed diuretic dose andNYHA functional class as additional independent predic-tors of mortality that provided incremental value to previ-ous scoring systems.13 Our study aims to make furtherprogress in this field, considering that patient profiles areevolving, specific therapies are now routinely prescribed,and survival is increasing. Moreover, whereas mortality remains the main con-cern of physicians treating ATTR-CM patients, short-term challenges of patients with ATTR-CM often revolvearound fluid management and heart failure decompensa-tions. Hospitalizations attributable to heart failure havebeen shown to worsen prognosis in ATTR-CM9 and arestrongly related with a decrease in quality of life,24 under-scoring the need to accurately identify those individualsat risk to closely monitor and adjust their diuretic therapyto prevent worsening heart failure episodes and improveprognosis. In fact, a recent study has demonstrated thatNT-proBNP progression and outpatient diuretic intensi-fication at 1 year are associated with an increased risk ofsubsequent mortality in ATTR-CM.25 Adrenomedullin (ADM) is a 52-amino acid peptidebelonging to the calcitonin gene-related peptide family.It is present in nearly all human tissues, with the highestconcentrations being found in the adrenal medulla, heart,lungs, and endothelium.20 In the setting of heart failure, the ADM gene is upreg-ulated in cardiac myocytes because of pressure and vol-ume overload. ADM acts as a vasodilator and stimulatesdiuresis and natriuresis, effectively reducing both preloadand afterload.26 Moreover, ADM plays a role in reducingcardiac remodeling and fibrosis.27 It also stabilizes theendothelial barrier, modulates its permeability, and exertsan anti-inflammatory effect. ADM could be of particularinterest in amyloidosis, as the disease has shown fre-quent vascular involvement, with perivascular depositsand capillary infiltration.28 In fact, elevated ADM levelshave been described not only in heart failure but also inother conditions in which permeability of vessels couldbe affected such as sepsis, COVID-19, and inflammatorydiseases.29 However, determination of ADM concentrations is lim-ited because of its in vitro instability, attributed to its shorthalf-life and rapid clearance from the bloodstream.30 Thisproblem was solved by measuring MR-proADM, a stablefragment of pro-ADM, in which concentrations accu-rately reflect those of ADM.31,32 Adlbrecht et al demonstrated that the prognostic valueof MR-proADM was higher than that of BNP in a cohort ### Page 11 of 786 patients with chronic heart failure.33 Furthermore,they observed that MR-proADM was a better predictor ofmortality in patients with nonischemic heart failure. Later,Von Haehling et al confirmed that MR-proADM was anindependent predictor of 12-month mortality in a groupof 501 chronic heart failure patients with MR-proADMadding prognostic value to NT-proBNP.20 In the present study, we demonstrate that MR-proADM behaves as an independent predictor formortality and for the composite end point of all-causedeath, worsening heart failure and heart transplant inpatients with ATTR-CM. Although MR-proADM hasnot been previously investigated in amyloidosis, ourfindings are consistent with the scarce evidence avail-able in heart failure. In the BACH trial (Biomarkers inAcute Heart Failure), Maisel et al demonstrated that forpatients presenting to the emergency department withdyspnea, MR-proADM identified those at higher riskof 90-day mortality, and that MR-proADM added prog-nostic value to BNP.34 In the VERifying DYspnea trial,Travaglino et al further confirmed its prognostic value,demonstrating that MR-proADM was a strong predic-tor of 90-day mortality in patients admitted for dys-pnea.35 Consistent with its prognostic role, our studydemonstrated the association between increased MR-proADM levels and the presence of multiple indicatorsof severity in ATTR-CM. To our knowledge, this is the first study to evaluate MR-proADM in ATTR-CM. Our findings highlight the promis-ing potential of this biomarker in this clinical scenario.This is particularly important considering the increas-ing life expectancy of patients with ATTR-CM and theimperative need to identify those at higher risk of heartfailure decompensation, who need closer monitoringand tailored diuretic treatment. We identified a threshold(MR-proADM ≥1.1 nmol/L) that predicts worse progno-sis and validated it in 2 independent cohorts: a real-worldcohort, reflecting everyday clinical practice, and a clinicaltrial cohort from the ATTR-ACT study. In both settings,MR-proADM was consistently associated with the inci-dence of adverse cardiovascular outcomes. Furthermore,MR-proADM could be used to improve patient selectionin new clinical trials, decreasing the number of patientsneeded to demonstrate clinical benefit in a scenario ofpatients already receiving specific therapies. Lastly, ourfindings open avenues for further research and bringthe opportunity to evaluate changes in this biomarker asshort-term indicators of deterioration that could assistclinicians when switching or adding specific therapies. ### Study Limitations In the derivation cohort, the number of patients whoreceived tafamidis was low, and both women and pa-tients with ATTRv were underrepresented. Heart failureevents were not available in one of the validation cohorts.MR-proADM is not a biomarker commonly used in clini-cal practice. However, several MR-proADM assays areavailable, which may allow rapid adoption in routine labo-ratory testing. Because this biomarker is not specific toheart disease, its applicability may be limited in the pres-ence of other conditions such as sepsis or COVID-19infection, which warrants further research. ### Conclusions In the present study, we demonstrate that MR-proADMis an independent predictor of all-cause mortality andthe composite end point of all-cause mortality, worseningheart failure and heart transplant in patients with ATTR-CM. MR-proADM improved prediction when added to theMayo, NAC, and Columbia staging systems. Our workpaves the way for tailored risk assessment and targetedmanagement strategies in ATTR-CM. ## ARTICLE INFORMATION Received October 15, 2025; accepted March 5, 2026. ### Affiliations Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda,IDIPHISA, Majadahonda, Spain (B.P.-A., M.B., E.G.-L., F.D., P.G.-P.). Centro Nacio-nal de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (B.P.-A., M.A.F.-R.,R.M.C., F.D., P.G.-P.). Cardiology Department, Hospital Universitari Germans Triasi Pujol, Badalona, Department of Medicine, Autonomous University of Barcelona,Barcelona, Spain (E.R.-L., A.C., M.R.-C., J.L., A.B.-G.). CIBERCV, Instituto de SaludCarlos III, Madrid, Spain (E.R.-L., J.N., E.G.-L., F.D., M.R.-C., J.L., A.B.-G., P.G.-P.).ICREC Research Program, Germans Trias i Pujol Research Institute (IGTP), Bad-alona, Barcelona, Spain (E.R.-L., B.M., A.B.-G.). Cardiology Department, Hospi-tal Clínico Universitario de Valencia, Universitat de Valencia, INCLIVA, Valencia,Spain (J.N.). The University of Queensland, Frazer Institute, Brisbane, Australia(M.A.F.-R.). Department of Biochemistry, Hospital Universitario Puerta de HierroMajadahonda, Majadahonda, Spain (A.F.-M., A.M.-G., A.J.-M.). Clinical Cardiovas-cular Research Laboratory for the Elderly (CCRLE), New York-Presbyterian/Columbia University Irving Medical Center, New York, NY (S.T., D.B., M.S.M.). Car-diovascular Institute, Oregon Health and Science University, Portland, OR (I.J.,A.M.). Clinical Biostatistics, Puerta de Hierro Biomedical Research Institute (IDI-PHISA), CIBERESP, Madrid, Spain (A.R.). Universidad Francisco de Vitoria (UFV),Pozuelo de Alarcón, Spain (P.G.-P.). ### Sources of Funding This work was supported by grants from the Instituto de Salud Carlos III(PI24/02093 and Centro de Investigacion Biomedica en Red en enferme-dades CardioVasculares (CIBERCV) grants 16/11/0432, 16/11/00420,16/11/00403), cofunded by European Regional Development Fund/EuropeanSocial Fund (“A way to make Europe”/ “Investing in your future”), and FundacionEugenio Rodriguez Pascual (FERP-2023-0019). The Centro Nacional Inves-tigaciones Cardiovasculares (CNIC) is supported by ISCIII, MCIN, the Pro-CNICFoundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). M.S.M. reports grant support from the National Institutes of Health(NIH; R01HL139671 and AG081582). ### Disclosures M.M. reports grants from Alnylam, BridgeBio, Intellia, and Ionis, and personal feesfrom Alnylam, Novo-Nordisk, Roche, Prothena Astra Zeneca, Akcea, and Intellia.A.M. reports research grants from Pfizer, Ionis, Attralus, and Cytokinetics, and feesfrom Cytokinetics, BMS, Eidos/BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam,Haya, Alexion, Akros, Prothena, BioMarin, AstraZeneca, and Tenaya. The otherauthors have nothing to disclose. ### Supplemental Material Supplemental Methods Tables S1–3 Figures S1–S4 ### Page 12 ## REFERENCES 1. Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, Basso C, Brucato A, BurazorI, Caforio ALP, Damy T, Eriksson U, et al. Diagnosis and treatment of car-diac amyloidosis: a position statement of the ESC working group on myo-cardial and pericardial diseases. Eur Heart J. 2021;42:1554–1568. doi:10.1093/eurheartj/ehab072 2. 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