Aimo, Alberto

Rapezzi, Claudio

Serenelli, Matteo

English

Archivio della ricerca della Scuola Superiore Sant'Anna

Early-stage amyloid transthyretincardiomyopathy: uncertainties andopportunitiesClaudio Rapezzi1,2*, Matteo Serenelli1, and Alberto Aimo 3,41Cardiologic Centre, University of Ferrara, Ospedale di Cona, Via Aldo Moro 8, 44124 Cona (Ferrara), Italy; 2Maria Cecilia Hospital, GVM Care & Research, Cotignola (Ravenna), Italy;3Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; and 4Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, ItalyOnline publish-ahead-of-print 26 May 2022This editorial refers to ‘Characteristics and natural history of early-stage cardiac transthyretin amyloidosis’, byS. Law et al., https://doi.org/10.1093/eurheartj/ehac259.Amyloid transthyretin cardiomyopathy (ATTR-CM) used to beconsidered a rare disorder whose diagnosis required a tissue biopsyand which had no treatment options. As a result, most cases werediagnosed only in late stages or remained undiagnosed. Over thelast few years, greater disease awareness, the introduction of an al-gorithm for non-invasive diagnosis,1 and the recent approval ofGraphical AbstractNatural history of amyloid transthyretin cardiomyopathy (ATTR-CM).The figure provides a schematic representation of the progressionof tissue amyloiddeposits, diseasemanifestations, the burdenofmorbidity andmortality,and the expected cost-effectiveness of tafamidis fromnormal ageing toNational AmyloidosisCentre (NAC) Stage III disease.HF, heart failure; HFpEF, heartfailure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NT-proBNP, N-terminal probrain natriuretic peptide.The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.* Corresponding author. Tel: +39 0532 239882, Email: claudio.rapezzi@unife.it© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail:journals.permissions@oup.comEuropean Heart Journal (2022) 43, 2633–2635https://doi.org/10.1093/eurheartj/ehac261EDITORIALDownloaded from https://academic.oup.com/eurheartj/article/43/27/2633/6593473 by guest on 28 July 2024tafamidis as the first specific treatment have led to a dramatic in-crease in the number of diagnoses of ATTR-CM, and particularlyits wild-type (wt) form. Studies trying to establish the prevalenceof ATTR-CM have pursued two main approaches: (i) the systematicassessment of subgroups with a high likelihood of overt disease[mainly heart failure (HF) with preserved ejection fraction and severeaortic stenosis]; or (ii) the screening of individuals with a high likeli-hood of subclinical disease (in particular carriers of TTR gene muta-tions, individuals operated on for carpal tunnel syndrome, or thoseundergoing bone scintigraphy for non-cardiac reasons). Several stud-ies have examined the natural history, predictors of outcome, and re-sponse to tafamidis of patients in the first group, while reliable dataon subjects with early disease are lacking.In this issue of the European Heart Journal, Law et al. provide novelevidence on the natural history of patients with untreated ‘early-stage’ ATTR-CM.2 This study is a retrospective analysis of patientsfrom the UK National Amyloidosis Centre (NAC) cohort (n=623) and the French Amyloidosis Mondor Network (n= 256).These patients had ATTRwt or ATTR due to the cardiac-specificp.V142I variant, NAC Stage I disease [N-terminal probrain natriuret-ic peptide (NT-proBNP) ≤3000 ng/L and estimated glomerular fil-tration rate (eGFR) ≥45 mL/min/1.73 m2], and were not receivingany disease-modifying treatment. The authors identified a Stage Iacorresponding to NT-proBNP ≤500 ng/L (or ≤1000 ng/L in thepresence of atrial fibrillation) and a daily loop diuretic equivalentdose,0.75 mg/kg. Survival free from all-cause death was comparedwith patients in Stage Ib (i.e. those with Stage I disease not meetingthe criteria for Stage Ia) and survival data on age- and gender-matched individuals from the UK. Individuals with stage IaATTR-CM had longer survival than those with Stage Ib disease,and not significantly different from that of the general population.Nevertheless, Stage Ia subjects displayed some evidence of diseaseprogression over a median follow-up of 28 months: for example,26% progressed to Stage Ib and 18% to Stage II, the percentage ofpatients with New York Heart Association class ≥II increasedfrom 62% to 82%, and median NT-proBNP increased by 145 ng/Lper year.2The authors should be congratulated for proposing new diagnos-tic criteria for early-stage ATTR-CM and for comparing—for thefirst time—the survival of individuals with early-stage disease vs.matched individuals from the general population. As with all studiesintroducing novel concepts, this study generates many questions thatmay prompt new investigations.What is the time-course of theprogression from asymptomaticcardiac disease to overt clinicaldisease?It is currently unclear how much time is needed for amyloid depositsto become large and confluent, then for extracellular spaces to en-large, and eventually for left ventricular (LV) pseudohypertrophyto develop. This lack of evidence translates, for example, into the va-gue recommendation that TTR mutation carriers be screened start-ing from10 years before the age of disease onset in affected familymembers.3 Most of the few data about the early stages of ATTR-CMcome from the follow-up of TTR mutation carriers, from subjectswith unexpected cardiac uptake of a bone tracer during a scintig-raphy requested for other reasons (who generally have ATTRwt),from patients with carpal tunnel syndrome, or from those with inci-dental finding of amyloid deposits on tissue specimens from differentkinds of surgery. Based on this sparse evidence, we can conclude that:(i) amyloid deposition in the transverse carpal ligament precedes by3–10 years the development of ATTR-CM; (ii) cardiac uptake ofbone tracers may precede (sometimes by several years) the develop-ment of LV pseudohypertrophy; and (iii) cardiac amyloid accumula-tion manifests first with subtle abnormalities in myocardialcontraction that can be detected through LV and possibly also leftatrial strain.4Plasma natriuretic peptides probably start to increase during earlydisease stages following the two triggers for release, namely in-creased myocardial wall tension and the toxicity of amyloid precur-sors and pre-fibrillary aggregates.5,6 The study by Law et al. showsthat NT-proBNP is a strong and independent predictor of outcomeeven in patients with Stage I disease, which is one of the reasons whythe investigators chose an NT-proBNP cut-off to discriminate twosubsets of Stage I patients with a different prognosis. Dedicated stud-ies would also be welcome to assess the role of contemporarytroponin assays, potentially able to detect cardiomyocyte damagefollowing amyloid deposition and myocardial tissue remodelling.What are the best criteria todefine early-stage ATTR-CM?As discussed by the authors, the definition of Stage Ia broadly reflectsthe entry criteria of clinical trials on ATTR amyloidosis, which in-cluded NT-proBNP cut-offs and a history of HF or clinical evidenceof HF (ATTR-ACT, ATTRIBUTE-CM, APOLLO-B, HELIOS-B,ION-CS2, and ITL-2001-CL-001).2 The identification of anNT-proBNP cut-off is further supported by the prognostic valueof NT-proBNP, as discussed above.2 On the other hand, the specificcut-off values of NT-proBNP and loop diuretic equivalent dose werechosen arbitrarily. Furthermore, the two variables provide partiallyoverlapping information on pulmonary and systemic congestion,and the loop diuretic dose introduces an element of subjectivity, asit may vary according to the policy of single centres and individualphysicians. Additionally, a combination of two dichotomous variablescan be easily evaluated in clinical practice, but provides a rather sim-plistic view of the patient’s status. Multidimensional scores combiningclinical, imaging, and laboratory data and considering continuous vari-ables might be considered at least in research settings for more ac-curate patient phenotyping and risk prediction.What is the life expectancy andthe natural history of elderlysubjects with early-stageATTR-CM?A strength of this study is the comparison with data from age- andgender-matched individuals from the same country. The first2634 EditorialDownloaded from https://academic.oup.com/eurheartj/article/43/27/2633/6593473 by guest on 28 July 2024interesting result is that there is no difference in overall survival dur-ing a median follow-up period of 21 months.2 This conclusion is sup-ported by several population studies searching for Val122Ilemutation carriers among black Americans,7–9 where the mutationstatus was not associated with shorter survival, even though patientswere much younger than in the present study (e.g. 62 years in theREGARDS cohort vs. 75 years in the cohort of Law et al.).2,7Therefore, we are starting to diagnose ATTR-CM even in older indi-viduals whose life expectancy will not be affected by this slowly pro-gressing disorder.While early-stage ATTR-CM does not seem to affect the lifeexpectancy of these patients, it still displayed an appreciable pro-gression during the ,2 year median follow-up. For example, aquarter of patients progressed from Stage Ia to Stage Ib, andslightly less than a fifth to Stage II or III.2 Accordingly, in the popu-lation studies on black American individuals, mutation carriershad a much higher risk of incident HF than matched indivi-duals,7–9 and this association was confirmed even after extensiveadjustment for potential confounders.7 An important limitationof these studies is that they simply excluded individuals withknown HF at baseline, and did not search for echocardiographicor laboratory signs of cardiac disease.7–9 We therefore do notknow how many of them would have met the NT-proBNP criter-ion for Stage Ia disease. Nonetheless, we may reasonably con-clude that subjects with early-stage disease have a higher riskof incident HF than age-matched individuals. HF hospitalizationis clearly a softer endpoint than all-cause mortality, but remainsan important determinant of morbidity and worse quality of lifein patients with ATTR-CM.10Translating these concepts from the clinical setting to the design ofrandomized clinical trials, we might conclude that reducing the ratesof HF hospitalization is a reasonable goal in subjects with early-stageATTR-CM, while efforts to reduce mortality are likely bound to fail.Does a disease-modifying therapyhave an acceptablecost-effectiveness profile inpatients with early-stageATTR-CM?Tafamidis is the only approved treatment for cardiac amyloidosis pa-tients without polyneuropathy. The criteria for prescription usuallyreflect the inclusion criteria of ATTR-ACT, which basicallycorresponds to the definition of Stage Ib ATTR-CM.11 Subjectswith Stage Ia disease were thus not enrolled in ATTR-ACT andare not eligible for tafamidis therapy because of the lack of demon-strated prognostic benefit from this drug. On the other hand, tafami-dis seemed more effective in less symptomatic patients, andtreatment initiation in early-stage ATTR-CM might be equally as ef-fective, at least when assessing the impact on HF hospitalization andquality of life. It is not unreasonable to propose clinical trials on pa-tients with early-stage disease (either ATTRwt or ATTRv with a car-diac phenotype) with the goal of reducing the burden of HFhospitalizations and improving the quality of life. A major hindranceto such trials is the high cost of these drugs making them not cost-effective even in patients with more advanced disease,12 wherethey can reduce mortality rates.Conflict of interest: none declared.References1. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al.Nonbiopsydiagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:2404–2412.2. Law S, Bezard M, Petrie A, Chacko L, Cohen OC, Ravichandran S, et al.Characteristics and natural history of early-stage cardiac transthyretin amyloidosis.Eur Heart J 2022;43:2622–2632.3. Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, Basso C, Brucato A, et al. Diagnosis andtreatment of cardiac amyloidosis: a position statement of the ESC Working Groupon Myocardial and Pericardial Diseases. Eur Heart J 2021;42:1554–1568.4. Rapezzi C, Aimo A, Pavasini R. Longitudinal strain in the management of cardiac ALamyloidosis: do we need it? Eur Heart J 2022;43:342–344.5. Castiglione V, Franzini M, Aimo A, Carecci A, Lombardi CM, Passino C, et al. Use ofbiomarkers to diagnose and manage cardiac amyloidosis. Eur J Heart Fail 2021;23:217–230.6. Bourgault S, Choi S, Buxbaum JN, Kelly JW, Price JL, ReixachN. Mechanisms of trans-thyretin cardiomyocyte toxicity inhibition by resveratrol analogs. Biochem BiophysRes Commun 2011;410:707–713.7. Parcha V, Malla G, Ivin MR, Armstrong ND, Judd SE, Lange LA, et al. Association oftransthyretin Val122Ile variant with incident heart failure among black individuals.JAMA 2022;327:1368–1378.8. Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, et al. Theamyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med2015;372:21–29.9. Buxbaum J, Alexander A, Koziol J, Tagoe C, Fox E, Kitzman D. Significance of theamyloidogenic transthyretin Val 122 Ile allele in African Americans in theArteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS)Studies. Am Heart J 2010;159:864–870.10. Aimo A, Rapezzi C, Perfetto F, Cappelli F, Palladini G, Obici L, et al. Quality of lifeassessment in amyloid transthyretin (ATTR) amyloidosis. Eur J Clin Invest 2021;51:e13598.11. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G,Waddington-Cruz M,et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.NEngl J Med 2018;379:1007–1016.12. Kazi DS, Bellows BK, Baron SJ, Shen C, Cohen DJ, Spertus JA, et al.Cost-effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy.Circulation 2020;141:1214–1224.Editorial 2635Downloaded from https://academic.oup.com/eurheartj/article/43/27/2633/6593473 by guest on 28 July 2024

Early-stage amyloid transthyretin cardiomyopathy: uncertainties and opportunities

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Early-stage amyloid transthyretin cardiomyopathy: uncertainties and opportunities

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