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The Truth Is Unfolding About Transthyretin Cardiac Amyloidosis

2019; Lippincott Williams & Wilkins; Volume: 140; Issue: 1 Linguagem: Inglês

10.1161/circulationaha.119.041015

1524-4539

Justin L. Grodin, Mathew S. Maurer,

Eosinophilic Disorders and Syndromes

HomeCirculationVol. 140, No. 1The Truth Is Unfolding About Transthyretin Cardiac Amyloidosis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Truth Is Unfolding About Transthyretin Cardiac Amyloidosis Justin L. Grodin, MD, MPH and Mathew S. Maurer, MD Justin L. GrodinJustin L. Grodin Justin L. Grodin, MD, MPH, 5323 Harry Hines Blvd, Dallas, TX 75390-8830. Email E-mail Address: [email protected] University of Texas Southwestern Medical Center, Dallas (J.L.G.). and Mathew S. MaurerMathew S. Maurer Clinical Cardiovascular Research Laboratory for the Elderly, Columbia University Medical Center, New York, NY (M.S.M.). Originally published1 Jul 2019https://doi.org/10.1161/CIRCULATIONAHA.119.041015Circulation. 2019;140:27–30This article is a commentary on the followingNatural History, Quality of Life, and Outcome in Cardiac Transthyretin AmyloidosisArticle, see p 16Transthyretin cardiac amyloidosis (ATTR-CA) was thought to be a rare, untreatable, terminal disease. This bygone refrain is rapidly being proven inaccurate. Noninvasive diagnostic techniques have broadened the understanding of affected populations, and novel therapies that reduce morbidity and mortality in ATTR-CA are rapidly emerging. Because of these innovations, we are embarking on exciting new horizons for the management of ATTR-CA. However, these strategies have needed further context within the natural history of this disease.In this issue of Circulation, Lane and colleagues1 conducted a cohort study aimed at clarifying the natural history of 1034 individuals with either hereditary (ATTRh) or wild-type (ATTRwt) CA referred to the United Kingdom National Amyloid Center (UK-NAC) between 2000 and 2017. The UK-NAC provides evaluation, diagnosis, monitoring, and management services for the national caseload of patients with amyloidosis, thereby affording a unique opportunity to characterize ATTR-CA in a cohort where referral bias may be less substantial than in other series.The observations from this report highlight the potential for recent advancements in cardiac and amyloid-specific imaging to overcome historical impediments to diagnosis and identify vulnerable individuals that might benefit from ATTR-specific therapies. All diagnoses of ATTR-CA were based on validated diagnostic criteria (biopsy-proven or with technetium-labeled bone scintigraphy coupled with required assessment for monoclonal proteins and genetic testing) and patients were followed on a protocol every 6 months thereafter. These follow-up visits included amino-terminal pro-B-type natriuretic peptide levels, electrocardiography, and echocardiography. Functional status via the 6-minute walk test and quality of life via the Kansas City Cardiomyopathy Questionnaire were added to each visit in 2010. In a subset of the cohort, hospital service use (inpatient, outpatient, and emergency department) was determined by using the data from the National Health Service in England.This analysis provides several notable observations informing the types of ATTR-CA and their natural history. First, there was a striking upsurge of new diagnoses of ATTR-CA from 2008 onward, driven largely by an increased recognition of ATTRwt. Increased recognition was likely the direct consequence of more frequent use of noninvasive imaging at the UK-NAC that included cardiac MRI and bone scintigraphy.2,3 Second, ATTRh-CA has a comparatively worse prognosis than ATTRwt. In addition, patients with V122I ATTRh had higher serial amino-terminal pro-B-type natriuretic peptide in comparison to non-V122I ATTRh or ATTRwt, suggesting that it may confer a more malignant myocardial phenotype. Third, the prognosis of individuals with ATTRwt diagnosed after 2012 (when bone scintigraphy was implemented as a diagnostic strategy) was better than among individuals with ATTRwt diagnosed in the preceding years. This observation is likely related to a lead-time bias (earlier detection of ATTR-CA) and it underscores the potential for noninvasive diagnostic strategies to recognize ATTRwt earlier in the disease when ATTR-specific therapies might be more beneficial (Figure). Fourth, the increasing healthcare utilization before establishing the diagnosis of ATTR-CA highlights substantial diagnostic delays. Even once the diagnosis was secured, regardless of genotype, ATTR-CA was associated with progressive declines in functional capacity and quality of life. This observation unfortunately parallels diagnostic delays for light-chain amyloidosis4 and should be a siren call for change.Download figureDownload PowerPointFigure. Conceptual model of ATTR-CA progression over time. Changes in various parameters are shown. The relative scale specific to each factor and time course are not proportional. Myocardial amyloid infiltration occurs before clinically manifest changes in ejection fraction, cardiac biomarkers, and renal function. Thus, most patients with ATTR-CA likely have a long latency period before declines in functional capacity, which can occur rapidly in the context of multiple hospitalizations for acute decompensated heart failure and arrhythmias. The ideal emerging therapeutic window for novel therapies is hypothesized to be before significant organ dysfunction has occurred and before rapid and potentially irreversible declines in functional capacity. *Biomarker Stage defined by the Mayo Clinic for ATTRwt as cardiac troponin T (<0.05 ng/mL) and amino-terminal pro-B-type natriuretic peptide (<3000 pg/mL) with stages I, II, and III defined as having both, one, or neither of the markers below the threshold, with a median survival of 66, 40, and 20 months, respectively, or by the UK-NAC for both ATTRwt and ATTRh with estimated glomerular filtration rate (eGFR) of 45 mL/min instead of troponin. Median survival was 69, 47, and 24 months in stages I, II, and III, respectively, with longer survival in ATTRwt than in ATTRh-CA. ATTR-CA indicates transthyretin cardiac amyloidosis; ATTRh, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; KCCQ, Kansas City Cardiomyopathy Questionnaire; 6 MWD, 6-minute walk distance; NYHA, New York Heart Association; QOL, quality of life; and UK-NAC, United Kingdom National Amyloid Center.Studies comparing the outcomes of patients with the most common heritable form of CA (V122I ATTRh) versus those with ATTRwt have been conflicting, but, in general, have shown a worse prognosis with the former, as shown in the present study.5,6 Although this prognostic difference had hypothetical biological underpinnings, residual confounding from differential access to care and socioeconomic factors between V122I subjects and ATTRwt remained a concern. At the UK-NAC, the median time from symptom onset to diagnosis was shorter (25 months) in ATTRh than in ATTRwt (39 months), which, when coupled with the more rapid increase in amino-terminal pro-B-type natriuretic peptide and decrements in quality of life, provides substantive evidence that the V122I genotype is more aggressive than ATTRwt. These observations highlight the role that more widespread use of genetic testing can play in identifying allele carriers who are at risk for ATTRh-CA, facilitating emerging therapies at a time earlier in the course of their disease, before they enter the phase of rapid progression.In the subset of patients with available data from the National Health Service in England, Lane et al observed steady increased healthcare usage in the years leading up to a formal diagnosis of ATTR-CA. This increasing use of hospital-based health care highlights the sobering number of missed opportunities to secure an accurate diagnosis of ATTR-CA. Once diagnosed, the hospital-based healthcare utilization appears to stabilize. However, quality-of-life observations from individuals with Kansas City Cardiomyopathy Questionnaire data within their first 12 months after diagnosis highlight ongoing burdens of disease characterized by significant physical impairments with concomitant limited social interactions despite high self-efficacy. Over the years that follow, there remains a progressive decline in quality of life mirrored by a progressive decline in exertional capacity.We are entering an era with a rapid emergence of therapeutic options for ATTR that have the potential to change the natural history of the disease. Two gene-silencing therapies reduce circulating transthyretin (TTR), and halt or slow the progression of ATTRh polyneuropathy: inotersen, an antisense oligonucleotide; and patisiran, a small interfering RNA.7,8 These treatments may have favorable cardiac effects in ATTRh-CA and ATTRwt-CA as well.9,10 Other treatments stabilize the TTR tetrameric structure preventing tetramer dissociation, which is the rate-limiting step in TTR amyloid fibril formation. Tafamidis is a small molecule engineered to bind to the thyroxine binding pocket of TTR and stabilizes the TTR tetramer. The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial demonstrated that tafamidis reduced mortality and cardiovascular hospitalizations in both ATTRwt-CA and ATTRh-CA along with a slowing of the decline in functional capacity and quality of life.11 Preliminary studies with AG10, another TTR-stabilizing molecule, have been promising and a phase 3 trial is underway (ClinicalTrials.gov: NCT03860935).12 Therefore, observations in the present study provide important context in how these therapies might influence the natural history of ATTR-CA. Both types of therapies work by inhibiting amyloid fibril formation and may therefore be more efficacious if administered earlier in the course of the disease when there is less cardiac dysfunction from amyloid deposits (Figure).Several significant unmet needs and unanswered questions remain, however. These include defining the optimal timing of initiating ATTR-CA therapies, determining comparative effectiveness between TTR silencers and TTR stabilizers, and clarifying the role of combination therapies. With the dramatically changing therapeutic landscape, early recognition of ATTR-CA will be critical. Approaches to identify the presence of ATTR-CA in at-risk populations have identified affected individuals in cohorts with tendinopathies,13 heart failure with preserved ejection fraction,14 and aortic stenosis.15 Given the potential to diagnose ATTR earlier in the course of the disease, more data will be needed to guide the decision on when to initiate treatment and which emerging treatment(s) to use at each stage of the disease. Although early recognition is key to leveraging emerging therapies, these uncertainties remain, underscoring the necessity of studies like the present report by Lane et al to unfold the truth about ATTR-CA.Sources of FundingDr Grodin receives grant support from the Texas Health Resources Clinical Scholarship. Dr Maurer receives grant support from National Institutes of Health grants R01HL139671-01, R21AG058348, and K24AG036778.DisclosuresDr Grodin receives consulting income from Pfizer. Dr Maurer receives consulting income from Pfizer, GSK, Eidos, Prothena, Akcea, and Alnylam, and his institution received clinical trial funding from Pfizer, Prothena, Eidos, and Alnylam.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Justin L. Grodin, MD, MPH, 5323 Harry Hines Blvd, Dallas, TX 75390-8830. Email Justin.[email protected]eduReferences1. 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Izumida T, Imamura T, Nakamura M and Kinugawa K (2021) Optimal Heart Rate and Prognosis in Patients with Cardiac Amyloidosis, Journal of Cardiovascular Development and Disease, 10.3390/jcdd8120182, 8:12, (182) Cotrina E, Vilà M, Nieto J, Arsequell G and Planas A (2020) Preparative Scale Production of Recombinant Human Transthyretin for Biophysical Studies of Protein-Ligand and Protein-Protein Interactions, International Journal of Molecular Sciences, 10.3390/ijms21249640, 21:24, (9640) Related articlesNatural History, Quality of Life, and Outcome in Cardiac Transthyretin AmyloidosisThirusha Lane, et al. Circulation. 2019;140:16-26 July 2, 2019Vol 140, Issue 1 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.041015PMID: 31549879 Originally publishedJuly 1, 2019 Keywordsquality of lifecardiomyopathiesamyloidosis, hereditaryEditorialsPDF download Advertisement SubjectsCardiomyopathyHeart Failure