Wild-Type Transthyretin Amyloid Cardiomyopathy
2015; Lippincott Williams & Wilkins; Volume: 133; Issue: 3 Linguagem: Inglês
10.1161/circulationaha.115.020351
ISSN1524-4539
Autores Tópico(s)Medical Imaging and Pathology Studies
ResumoHomeCirculationVol. 133, No. 3Wild-Type Transthyretin Amyloid Cardiomyopathy Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWild-Type Transthyretin Amyloid CardiomyopathyA Missed Cause of Heart Failure With Preserved Ejection Fraction With Evolving Treatment Implications Peter P. Liu, MD and David Smyth, PhD Peter P. LiuPeter P. Liu From University of Ottawa Heart Institute, ON, Canada. and David SmythDavid Smyth From University of Ottawa Heart Institute, ON, Canada. Originally published11 Dec 2015https://doi.org/10.1161/CIRCULATIONAHA.115.020351Circulation. 2016;133:245–247Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 12, 2016: Previous Version 1 Heart failure is a devastating but heterogeneous disease. Although ischemic heart disease and hypertension account for a significant portion of heart failure, the precise cause and pathophysiology of many other forms of heart failure are less clear. This is particularly underscored by our repeated failed attempts to identify effective treatments for heart failure with preserved ejection fraction (HFpEF). It is only through accurate etiologic diagnoses and understanding of the causes of heart failure, in particular HFpEF, associated with high mortality, that we can offer more precisely targeted therapies in the future.1Article see p 282Amyloid heart disease is a devastating cause of heart failure, resulting from the deposition of misfolded or misassembled protein fibrils (amyloid) in the cardiac extracellular matrix. Amyloid deposition impairs diastolic and subsequently systolic cardiac function and has been thought to be rare. Amyloid heart disease could be secondary to hematological disorders such as multiple myeloma with deposition of excessive circulating immunoglobulin light chains in the heart (AL amyloidosis) or abnormal proteins resulting from systemic inflammatory disease leading to production of amyloid A, an acute-phase reactant (AA type; Figure 1).Download figureDownload PowerPointFigure 1. Comparison of the subtypes of amyloid cardiomyopathy in terms of cause, specific features, survival, prognostic factors, and examples of therapy. The chart includes the common types of systemic amyloidosis (AL and AA forms), as well as the transthyretin (TTR) varieties, including the wild-type form (ATTRwt). AA indicates amyloid A; AL, amyloid caused by light-chain deposition; ASO, antisense oligonucleotide; BNP, brain natriuretic peptide; HR, heart rate; LVEF, left ventricular ejection fraction; siRNA, small interference RNA; and Tx, transplantation.However, more recently, there has been increased recognition of cardiac amyloidosis caused by the deposition of transthyretin, which is a circulating 127–amino acid protein made in the liver to transport hormones such as thyroxine and retinol. Transthyretins are prone to form fibrils because of either genetic mutations in the transthyretin protein (ATTRm), leading to abnormal variant protein misfolding and aggregating,2 or the increasing recognition of wild-type transthyretin (ATTRwt), which can also be misassembled, leading to aggregate formation, particularly in older patients. ATTRwt has also been referred as senile or age-related amyloidosis. The characterization of this latter underrecognized condition causing heart failure is the focus of the study by Connors et al3 in this issue of Circulation.Although mutated TTRm protein can misfold and lead to protein aggregation, it is less clear why wild-type transthyretin, which is theoretically the normal protein, would also develop amyloid deposition. It is relevant to note that transthyretin normally occurs as a tetramer to create the pockets for thyroxin binding. However, in ATTRwt, posttranslational modifications of the transthyretin or inappropriate chaperone production in the liver can lead to failure of proteasomal clearance of unfolded transthyretin. This can lead to the excess accumulation and subsequent aggregation of amyloid fibrils.Connors and colleagues published here a large cohort involving only ATTRwt. Judging by the frequency of ATTRwt in their total referral population, the data suggested that ATTRwt, or senile amyloid cardiomyopathy, is likely much more prevalent than previously thought. In fact, it may be a more common cause of HFpEF in elderly patients but is currently largely undiagnosed. Indeed, this is borne out with observations from autopsy studies. Cornwell observed in 85 autopsies of patients >80 years of age that ATTRwt or senile amyloid deposits in the heart occurred in 25% of the patients.4 This was corroborated in a prospective Finnish autopsy series involving 256 octogenarians, in which the prevalence of ATTRwt deposits was 25%.5 The Finnish study also noted increased association with myocardial infarction and other cardiac complications. With the rapidly rising elderly population in the world, ATTRwt will rapidly evolve to be the most common form of amyloid heart disease.In this study published in Circulation, Connors and colleagues diagnosed and followed up 121 patients with biopsy-proven ATTRwt over 20 years. This work from the Amyloidosis Center at Boston University (BU) has been the vision of its late director, Dr David Seldin, and this publication is truly a tribute to his lifetime dedication.As is typical of ATTRwt or senile systemic amyloidosis, this cohort included mainly older patients, with commonly observed male predominance (98%) and a median age of 75.6 years at inception. The majority of patients presented with typical features of diastolic heart failure or HFpEF, with dyspnea on exertion (86%), peripheral edema (64%), and atrial fibrillation (67%). Interestingly, 46% of patients had a history of carpal tunnel syndrome, which may be a clue of local transthyretin deposition and can predate cardiac involvement by several years. These patients had significant accompanying comorbidities, including coronary disease (31%) and malignancies (34%).The important laboratory findings included elevated brain natriuretic peptide (mean, 482 pg/mL) and modestly elevated troponin (median, 0.126 ng/mL) and uric acid (8.2 mg/dL). Of note, 10% of the patients had monoclonal gammopathy, yet there was no evidence of immunoglobulin light chains on biopsy, underscoring the importance of obtaining tissue for proper amyloid protein diagnosis. Echocardiogram demonstrated increased relative wall thickness and left atrial dilation, and 100% of the patients had advanced diastolic dysfunction. Of particular note is their limited functional capacity, with mean maximum o2 very low at 13.5 mL·min−1/kg−1.One of the important observations in this series is the patients' poor outcome. In this cohort, the Kaplan-Meier 5-year survival was 35.7%, much worse than a heart failure cohort of a similar age (eg, in the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors With Heart Failure [SENIORS] study, the average age was 76 years, the 20-month survival was 91%, and the imputed 5-year survival would be ≈72% in the placebo group).6 The cause of death was indeed heart failure in 67% of the patients. The most important predictors of poor outcome included elevated serum brain natriuretic peptide, high uric acid, decreased left ventricular ejection fraction, and increased relative wall thickness. These parameters reflected directly the severity of the underlying disease and provided potential surrogate end points to evaluate novel therapies.Another comparable series of patients with ATTRwt was published earlier by Pinney et al7 from University College of London in the United Kingdom. This cohort included 102 biopsy-proven ATTRwt patients. Compared with the BU cohort, the UK cohort showed similar male dominance (88% in the UK versus 98% in the BU group), dyspnea as the commonest presenting symptom, accompanied by atrial fibrillation (43% versus 67% in BU), and a similar history of carpal tunnel syndrome (48.5% versus 46%). However, the UK patient population compared with the BU population had a slightly younger presentation age (73 versus 76 years), milder symptoms (majority in New York Heart Association class I or II), and much lower median natriuretic peptides (N-terminal pro-brain natriuretic peptide, 295 pg/mL in the UK cohort; brain natriuretic peptide, 411 pg/mL in the BU cohort). This may explain why the median survival in the UK cohort was longer at 6.1 years compared with 4.6 years in the BU cohort. The UK cohort likely represented a slightly younger patient population diagnosed earlier with milder disease at the time of diagnosis. Many clinical features are shared, and overall, the survival is still extremely poor for both groups. This finding also suggests that earlier recognition and diagnosis are possible for ATTRwt patients.The diagnosis of amyloidosis is usually made by the identification of amyloid deposits with Congo red staining, demonstrating birefringence under polarized light (Figure 2). This can be complemented by immunohistochemistry, protein electrophoresis, or mass spectrometry to identify the type of amyloid involved. Cases of familial ATTRm can also be diagnosed with gene sequencing, but the type of amyloid protein deposited and clinical or genotype information may not always agree, so actual analysis of the amyloid protein deposition is still the most accurate means of diagnosis. Although echocardiography is the gold standard for the evaluation of cardiac size, function, and most important, wall thickness, radionuclide imaging has become an important addition to the toolbox for diagnosis. Earlier nuclear scans with bone imaging agents such as Tc-99m-pyrophosphate or Tc-99m-methyl diphosphonate could demonstrate cardiac amyloid involvement but had only modest sensitivity or specificity. More recently, the newer 3,3-diphosphono-1,2-propanodicarboxylic acid has shown a significant preferential uptake in ATTR cardiomyopathies and much less in AL hearts.8 With the newly available 18F-aV-45 (florbetapir) as a specific amyloid protein–labeling positron emitting tracer, future diagnostic strategies with nuclear imaging may help to diagnose amyloid heart disease earlier, when biopsy is not immediately available or by patient preference.Download figureDownload PowerPointFigure 2. Diagnostic workup pathway of patients suspected of amyloid cardiomyopathies. Clinical presentation includes heart failure symptoms typical of heart failure with preserved ejection fraction. Patients may also be referred because they have known systemic amyloid, and the question of cardiac involvement needs to be clarified. After imaging confirmation, the patient should undergo cardiac biopsy or peripheral tissue biopsy. The tissue should be stained with Congo Red and subjected to protein analysis to confirm the identity of the amyloid protein. AL indicates amyloid caused by light-chain deposition; ATTRm, amyloid caused by mutant or variant transthyretin; ATTRwt, amyloid caused by wild-type transthyretin; CMR, cardiac magnetic resonance; EF, ejection fraction; Func'n, function; LC/MS, laser capture liquid chromatography mass spectrometry; LGE, late gadolinium enhancement; r/o, rule out; Rx, therapy; Th, thickness; and TTR, transthyretin.The major reason that this study is particularly important and timely is that we are now on the verge of potential new breakthroughs in therapies for amyloid disease, particularly related to transthyretin subtypes. Previously, the only options for amyloid diseases were chemotherapy for light chain amyloid (AL type) or liver transplantation for ATTRm or ATTRwt. Liver transplantation has initially generated significant optimism because of improved survival and reduction in circulating transthyretin production. However, subsequent follow-up revealed that cardiac and neurological amyloid deposition can still continue with the production of TTRwt in the donor liver.However, recent exciting options have emerged that directly address the biochemistry of amyloid production or protein stability.9 RNA-targeted therapies aimed at the reduction of transthyretin production include antisense oligonucleotides targeted to mRNA of transthyretin. Phase I studies demonstrated the suppression of transthyretin protein production by a remarkable 75%, and the agent is relatively safe. A phase II/III trial is now ongoing. An alternative strategy to reduce transthyretin production is via silencing RNA (siRNA) therapies. Revusiran is a glycoprotein-conjugated siRNA targeted to transthyretin mRNA in hepatocytes. Revusiran evaluated in a phase II study showed a reduction in serum transthyretin of >85% in both ATTRwt and ATTRm cardiomyopathy patients, with a favorable cardiac biomarker profile.10 The evaluation of revusiran in cardiac amyloidosis for both familial ATTR and ATTRwt in phase III trial is ongoing.An alternative strategy to treat ATTR is to stabilize the tetrameric structure of transthyretin with small molecules to prevent dissociation into unstable monomeric units that can in turn form the amyloid β pleated sheets. Tafamidis meglumine is the first approved drug for ATTR that binds to the thyroxine-binding domain to stabilize the tetramer. Tafamidis has been found to reduce disease progression in ATTR patients in terms of neuropathy. There have been no definitive trials of Tafamidis in ATTR cardiomyopathy, even though a phase III ATTR outcome study is ongoing.An alternative small molecule is diflunisal, which can also stabilize transthyretin by improving the antiaggregating effect of clusterin on transthyretin monomers.11 Diflunisal is a nonsteroidal anti-inflammatory agent for arthritic pain available by prescription. A study from Japan demonstrated that diflunisal administration for 24 months in patients with transthyretin stabilized both neurological and cardiac function progression. Another repurposing randomized trial demonstrated that in patients with familial amyloid polyneuropathy, Diflunisal reduced the rate of neurological progression compared to placebo over a period of 2 years.12 The approval status of this agent is not currently clear.With these exciting potential therapies on the horizon, the outlook for amyloid heart disease is rapidly changing. The Connor et al study alerts us to the importance of recognizing ATTRwt early, particularly in elderly patients presenting with symptoms of HFpEF. This study also emphasizes the importance of making the correct diagnosis early. Both the practicing physician and potential amyloid referral centers need to be alerted to this changing epidemiology. This is an exciting example of how we may finally approach the HFpEF with greater insight and with an understanding of the disease pathophysiology in a significant high-risk subgroup of patients. Although their outcomes are very poor at the present time, the range of options of new therapies being tested gives us hope that we are on the threshold of being able to offer precision therapy for our patients with HFpEF.Sources of FundingThis was work was supported in part by grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation, and Genome Canada.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Peter P. Liu, MD, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON K1Y 4W7, Canada. E-mail [email protected] or [email protected]References1. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study.N Engl J Med. 2006; 355:260–269. doi: 10.1056/NEJMoa051530.CrossrefMedlineGoogle Scholar2. Ruberg FL, Berk JL. 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Grogan M, Scott C, Kyle R, Zeldenrust S, Gertz M, Lin G, Klarich K, Miller W, Maleszewski J and Dispenzieri A (2016) Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System, Journal of the American College of Cardiology, 10.1016/j.jacc.2016.06.033, 68:10, (1014-1020), Online publication date: 1-Sep-2016. January 19, 2016Vol 133, Issue 3 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.115.020351PMID: 26660283 Originally publishedDecember 11, 2015 Keywordscardiomyopathytreatment outcomeamyloidheart failureEditorialsPDF download Advertisement SubjectsCardiomyopathyHeart FailureMortality/Survival
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