key: cord-1012787-vmu09qie
authors: Garcia‐Pavia, Pablo; Bengel, Frank; Brito, Dulce; Damy, Thibaud; Duca, Franz; Dorbala, Sharmila; Nativi‐Nicolau, Jose; Obici, Laura; Rapezzi, Claudio; Sekijima, Yoshiki; Elliott, Perry M.
title: Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy
date: 2021-05-24
journal: Eur J Heart Fail
DOI: 10.1002/ejhf.2198
sha: 75c41180ce34f6e8f61723c9ba5e160b7b077d22
doc_id: 1012787
cord_uid: vmu09qie

Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a life‐threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR‐CM has stimulated increased awareness of the disease and patient identification. Stratification of patients with ATTR‐CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best‐practice guidance. In this report, experts with experience in treating amyloidosis and ATTR‐CM developed consensus recommendations for monitoring the course of patients with ATTR‐CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR‐CM will help to elucidate, refine and define these and other measurements.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening condition that is characterized by deposits of amyloid protein in the extracellular space of the myocardium, causing progressive infiltrative cardiomyopathy. 1,2 ATTR-CM is characterized by increased left ventricular (LV) wall thickness and diastolic dysfunction, with around a third of patients showing a restrictive filling pattern. 3 ATTR-CM presents in two predominant phenotypes: variant ATTR-CM (ATTRv), which is a hereditary form of the disease caused by mutations in the transthyretin (TTR) gene that can present as a multisystem disease in people from early middle age onwards; and wild-type ATTR-CM (ATTRwt), which predominantly affects the heart in isolation and typically affects men over 60 years of age, but is also found in women. 3, 4 The early stages of the disease manifest as heart failure (HF) with preserved ejection fraction 5 and may mimic hypertensive heart disease 3 or hypertrophic cardiomyopathy. 6 The natural history of ATTR-CM is variable, 7 particularly in hereditary forms where genotype influences the likelihood (and predominance) of cardiac involvement 7 but prognosis, if untreated, is poor with a median survival time from diagnosis of 3.6 years, 4 and 2.6 years for patients with V122I genotype. 8 . Traditionally, ATTR-CM has been considered to be a rare disease; however, recent data suggest that the prevalence may be substantially higher than previously assumed. 2, 9, 10 Historical underdiagnosis means that the natural history of the disease remains uncertain, with data limited to small observational cohorts and latterly to the placebo arm of clinical trials. Nevertheless, it is clear that the disease progresses silently and that diagnosis often follows presentation with late-stage cardiac manifestations. 8, 9, 11 It is hoped that with improved diagnosis and heightened awareness, ATTR-CM can be detected earlier, allowing more precise patient stratification and profiling with regard to disease progression at all stages.

Several red flags that support ATTR-CM suspicion and techniques that facilitate earlier diagnosis have been identified and these have assumed greater importance with the availability of disease-modifying treatments that improve clinical outcomes. 12, 13 Parameters that change with ATTR-CM disease progression span several domains, such as functional capacity, quality of life (QoL), laboratory biomarkers and cardiac imaging, and these require multidisciplinary expertise for their interpretation. 7 However, there is a lack of guidance on the use of potential disease markers in monitoring disease progression. Several models using independent measures for estimating prognosis in ATTR-CM are available To address this unmet need, a group of international experts in cardiac amyloidosis elaborated a series of recommendations for the monitoring of patients with ATTR-CM. The document is based on two surveys and two expert panel discussions, in which the experts provided experience-based opinions on the tests and biomarkers that they felt to be most useful and feasible for long-term assessment of ATTR-CM patients. This report summarizes the group's recommendations, including the thresholds for defining disease progression (Graphical abstract).

A panel of experts from Europe (Austria, France, Germany, Italy, Portugal, Spain and UK), Japan and the USA were convened in sponsored meetings. No participant was appointed by a national society or by a regulatory authority.

The experts were asked to complete two surveys and to agree on a final list of recommended clinical parameters deemed to be feasible and clinically meaningful when monitoring disease progression in ATTR-CM. In survey one, experts were asked to list key measurable clinical features for longitudinally assessing disease status in patients with ATTR-CM that they either used or would recommend. In survey two, experts were asked to rank the list of features and to outline the tools/techniques/investigations they would use to measure change in each clinical feature; they were also asked to describe the frequency and threshold for minimally important change for each measurement. Following completion of the surveys, panel discussions were held in which experts explored the value of individual parameters and achieved consensus on the clinical indicators and thresholds that inform on change in ATTR-CM. Subjectivity, standardization and sensitivity were considered, particularly where lack of standardization and inter-and intra-subject variability could impact consistency. To the best of our knowledge, this is the first time that a set of measurement tools has 

The surveys identified many candidate clinical features for monitoring patients with ATTR-CM, which are listed in the Appendices. During consensus discussions, the list was refined and defined using thresholds and frequency of measurements (Appendices 1-3). By consensus, this set of 11 measurable features, was recommended across three separate domains: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters ( Table 2) . While a change in each clinical feature was considered meaningful, worsening in any single marker was insufficient to define disease progression and at least one marker in each of the three domains was required.

Heart failure-related hospitalizations

The number of HF decompensation-related hospitalizations 16 requiring intravenous diuretic treatment 17 is a meaningful indication of disease progression and is used as a common endpoint in HF and ATTR-CM trials. 13 The recommended threshold for this parameter is one or more hospital admissions during a 6-month period, while the absence of any hospitalizations is considered stabilization of ATTR-CM during this period. The panel acknowledged that other reasons for hospitalizations -including pacemaker implantation due to rhythm disturbances and arrhythmias/syncope [if related with arrhythmias on electrocardiogram (ECG)/Holter] are well-established markers of progression. As hospitalization for arrhythmic/conduction disturbances would qualify under two domains, the panel aimed to avoid overestimation of a single parameter. While the experts agreed that the use of intravenous diuretic therapy (in both inpatient and outpatient settings) was a better indicator of disease progression than an increase in the use of oral diuretics, the dose of diuretic is a strong predictor of outcome in HF studies 18 and an independent predictor of mortality in ATTR-CM patients 15 ; moreover, peripheral oedema, observed as an increase in weight or ankle, leg and foot circumference, is a significant change that patients can monitor daily, 19 in addition to assessments at any hospital visits.

The exertion required to produce symptoms. Considered a cornerstone of clinical assessment of HF status, the NYHA classification is commonly used to determine eligibility status in clinical trials. 20 Although easily implemented in everyday practice, HF is more complex and multifactorial than the four classes described by this tool. Subjectivity and a lack of detail have meant that use of the NYHA classification to assess disease status has been questioned. 18,20 NYHA classification depends on patient self-reporting and physician examination, and its use is associated with risks of inter-and intra-subject variability. 18, 19 Although NYHA class has been shown to be prognostic in ATTR-CM, 20, 21 the group decided that it lacks sensitivity as a standalone tool for detecting subtle progression of ATTR-CM in individual patients, and therefore should be interpreted in a multiparametric approach with other markers 18 ; it was also recommended that NYHA measures should be made after 30 days of stability, as defined by stable symptoms. In ATTRv patients with overlapping phenotypes, NYHA classification may be limited in the assessment of motor disabilities caused by polyneuropathy.

Quality of life assessment, using tools such as EuroQol five dimensions (EQ-5D), the Kansas City Cardiomyopathy Questionnaire (KCCQ), is an established chronic disease measure 22 that is considered an essential indicator of response in HF treatment. 23 The Hospital Anxiety and Depression Scale (HADS) provides valuable patient insight, although it has not been validated specifically in the ATTR-CM population. In addition to being important endpoints for treatment trials, QoL assessments provide valuable learnings for patient engagement and education and may also help guide thresholds and cut-offs for different markers.

The KCCQ includes domains of physical and social limitations, symptoms and self-efficacy, using either an improvement or a reduced decline in QoL; this tool has been employed in randomized controlled trials (RCTs), including a recent evaluation of tafamidis in ATTR-CM. 10,13 A significant reduction in KCCQ decline was found in tafamidis-treated patients vs. placebo in the ATTR-ACT study 13 ; in the placebo arm of this study, KCCQ decline was greater in ATTRv patients than ATTRwt patients, and the placebo group also demonstrated higher mortality and increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels over time in ATTRv compared with ATTRwt. 10 In isolation, QoL measurements are subjective, and defining thresholds using these measures for patient management is a challenge; therefore, experts proposed that QoL should be used in concert with other measures to confirm stability or progression and, in this way, facilitate earlier detection of ATTR-CM progression. It should be noted that without the dedicated teams and resources provided in a research setting, routine QoL assessments may be too time-consuming for a typical clinic and patients may tire of repeated questionnaires. The KCCQ provides patient-centric data and can be used to monitor changes in disease status but training is required to improve physicians' understanding of the instrument 24 and where possible, disease-specific QoL tools should be used.

Physical assessments such as the number of meters walked in 6 min (6MWT) are an objective way to detect disease severity, progression and treatment effects 10,25 : for example, in the ATTR-CT study, 6MWT showed a reduced decline in tafamidis-treated patients compared with those receiving placebo. 13 However, because of logistical constraints, these tests tend to be performed in research settings more than routine clinical practice. 10, 25 Frailty is an important domain, particularly in elderly and multi-comorbidity patients; it is associated with higher risk of mortality and hospitalization in older patients with chronic HF. 26 if already being performed to assess physical function -may be helpful for stratifying frailty in ATTR-CM patients and determining prognosis. 26 Because formal frailty measurements are currently difficult to incorporate into routine clinics, these were not part of the recommended criteria in Table 2 ; however, they form an important part of patient examination.

NT-proBNP measurement is a reference biomarker for determining the probability of HF 27 ; moreover, owing to its low cost and easily interpretable results, it is feasible in routine clinical practice. NT-proBNP measurements are also deemed to be useful measures of disease progression 14 -as demonstrated in the placebo arm in the ATTR-ACT trial 10 and amyloidosis staging systems. 4 Where NT-proBNP measurements are not possible, B-type natriuretic peptide (BNP) can also be used to determine risk and predict outcomes in HF with reduced ejection fraction. It should be noted, however, that these peptides present in different ratios, with NT-proBNP levels more than six times higher than BNP in patients with HF with reduced ejection fraction and that BNP has been less studied in ATTR-CM. 28 Caution is advised when measuring NT-proBNP, as increased levels occur with renal failure and atrial fibrillation, 29, 30 which could impact on the interpretation of changes as evidence of ATTR-CM progression. In this regard, it should be noted that the relationship between NT-proBNP and estimated glomerular filtration rate is complex, reflecting a combination of cardiac and renal factors. 14 Given that analytical variability and biological variability affect the precision of this marker, 31 the panel recommended using both relative (30%) and absolute (300 pg/mL) increases in NT-proBNP to ensure that progression can be detected in both early-stage and more advanced patients. Proposed thresholds for NT-proBNP variation may be updated as more information becomes available. The experts stressed that biomarker measurements should be interpreted following 30 days of clinical stability, without a change in diuretic dose, and under the same heart rhythm (i.e. sinus or atrial fibrillation) as when previously examined. Otherwise, NT-proBNP should be interpreted accordingly.

Persistent elevation of cardiac troponin levels is suggestive of myocardial damage and may have prognostic value for ATTR-CM. 32 The standardization of absolute cardiac troponin levels, however, is an ongoing issue -generations of troponin assays developed by different manufacturers have confounded its use, with different centres preferring particular assays. 14 Furthermore, the association between absolute troponin value changes and changes in disease status is unknown, making it unclear what constitutes significant change. As patients with ATTR-CM are often clinically stable for years, 7 and because troponin levels may be in the reference range for long durations, a step change may not be suitable for patients with early stages of the disease. Therefore, this panel of experts believes that a 30% relative increase, using a high-sensitivity assay, would be a better indication of ATTR-CM progression than a pre-specified absolute level. Nevertheless, reduced troponin clearance in patients with concomitant HF and chronic kidney disease suggests that troponin measurements are also affected by renal function, 33, 34 underpinning the need for caution in interpreting such data, particularly in multimorbid patients.

Advanced clinical staging systems ( Table 1 ) allow documentation of changes and associations between biomarker levels, clinical and physical functioning, and QoL. Because the Mayo Clinic staging system was derived only for ATTRwt patients and the Columbia system includes functional parameters that are separately evaluated in the functional domain, the group agreed that these staging systems were less suited for our proposed model of monitoring progression of ATTR-CM. Moreover, the UK National Amyloidosis Centre (NAC) system described by Gillmore et al. 14 is currently the only staging system that has been shown to predict survival throughout the natural history of ATTR-CM 35 and comprises features from only the 'biomarkers and laboratory markers domain', therefore it was agreed that a change in the NAC score would be a helpful indication of disease progression in ATTR-CM. 4, 14, 35 

Due to low costs, as well as ease of image acquisition and interpretation, echocardiography is the universal imaging tool for cardiac amyloid assessment and plays a crucial role in monitoring disease progression 1 ; however, there is a need for clear and objective thresholds with regard to ATTR-CM progression criteria. Experts recommended that trends in disease progression should be identified and defined using serial measurements, and that findings should be interpreted in the context of other clinical examinations. RCT data may help to define thresholds for disease progression when long-term data on responders vs. non-responders becomes available.

Due to the capacity for serial measurements, the panel recommended that physicians simultaneously collect a range of echocardiography parameters that provide meaningful indications of ATTR-CM worsening; for example, stroke volume, inferior vena cava diameter, Doppler assessment including E/e' and transmitral flow, global longitudinal strain (GLS) and pericardial effusion.

Based on clinical trial data in which 8% of patients experienced ≥2 mm increase in LV wall thickness, 36 experts agreed that this threshold was suggestive of disease progression, whereas changes of a lesser magnitude may represent measurement error. However, such changes occur slowly and so are less likely to be useful in guiding short-term management decisions. Confounders such as systemic hypertension should also be considered when assessing LV wall thickness. Routine measurement of LV systolic function should be assessed with ≥5% decreases in LV ejection fraction or as determined from the ATTR-ACT trial data. 13 Indeed, these measures may be better indicators of ATTR-CM progression than LV wall thickness. LV GLS has also been shown to diagnose LV dysfunction in ATTR-CM at the early stages of the disease 37 and to be diagnostically accurate when differentiating cardiac amyloidosis from other aetiologies. 38 Based on linear extrapolations of findings from the APOLLO trial and ATTR-ACT, the panel recommended that a ≥1% increase in GLS was indicative of disease progression. 13, 36 Diastolic dysfunction in conjunction with wall thickening leads to restrictive cardiomyopathy 39 ; therefore, echocardiographic detection of diastolic worsening should be routinely performed, with the caveat that it may be altered by changes in fluid status, heart rate and heart rhythm. The value of different echocardiographic parameters varies according to disease stage; for example, early disease markers include LV strain and low-grade diastolic dysfunction, whereas late markers comprise LV ejection fraction, right ventricular systolic function, restrictive LV filling, reduced myocardial contraction fraction, increased LV mass and LV wall thickness. 40, 41 The recommended testing frequency of 6-12 months using echo agrees with published consensus statements on ATTR-CM imaging. 42

Using a standard 12-lead ECG, ATTR-CM can be characterized by a 'pseudo-infarct' pattern of Q-wave or T-wave changes or low QRS voltage. 1, 21 The development of atrioventricular (AV) block -particularly advanced AV block, and PR interval prolongation >20 ms -were considered meaningful changes in patients with ATTR-CM that signal disease progression 43 and may appear in isolation or together with bundle branch block pattern. The appearance of left bundle branch block or trifascicular block may also be indicative of disease worsening; however, because conduction disturbances are often present before diagnosis, 44 these measures may be inconclusive in isolation. Moreover, 24-h ambulatory ECG monitoring was considered a pragmatic recommendation for the detection of atrial fibrillation and conduction disturbances. In some individual patients with paroxysmal symptoms suggesting arrhythmia, more prolonged monitoring may be appropriate. 45, 46 Indications for permanent pacing, such as sinus node dysfunction, atrial fibrillation with a slow ventricular response and AV block also indicate disease progression.

As a pivotal diagnostic tool in ATTR-CM, cardiovascular magnetic resonance (CMR) using native T1 mapping and T1 with late gadolinium enhancement (LGE) is used for tissue characterization and measurement of extracellular volume (ECV). 47 Cine CMR is also more reproducible and accurate for measuring both LV geometry and functional parameters than echo measurements. 7, 48, 49 ECV has prognostic value in ATTR-CM, 50,51 but its use as a measure of treatment response requires validation. Although CMR is contraindicated with some pacemakers, new conditional devices enable imaging where necessary. However, based on costs, availability, and the lack of serial data in ATTR-CM, CMR was not included in the progression criteria. When available, long-term treatment data will clarify a future role for CMR and it is likely that interval scanning may be an important aspect of disease monitoring; for example, recently a biennial CMR screening was recommended in a consensus recommendations document for ATTR-CM. 42

Quantitative cardiac single photon emission computed tomography/positron emission tomography (SPECT/PET) using bone avid radiotracers, 99m Tc-pyrophospate (PYP), 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) and 99m Tc-hydroxymethylene diphosphonate (HMDP) are robust non-invasive diagnostic tools that are currently embedded in routine ATTR-CM diagnosis. [52] [53] [54] Recent findings demonstrated suboptimal sensitivity of DPD scintigraphy in patients carrying the early-onset Val50Met (formerly Val30Met) variant and other rarer genotypes like Phe64Leu, suggesting that the accuracy of the technique may be influenced by the ATTRv genetic variant. 55, 56 Although these tools play an important role in identifying early ATTR-CM, their value in assessing the progression of ATTR-CM is not fully elucidated, and therefore the expert group did not make a recommendation for their use in disease monitoring. 7 The same is true for other amyloid-specific radiotracers, such as 11 C-Pittsburgh compound B and 18 F-florbetapir. [57] [58] [59] [60] [61] 

There remains a need for practical clinical evaluation tools that are feasible to conduct every 6-12 months; for example, CMR, radionuclide imaging and QoL measures may be more challenging to perform, whereas clinical examination, NYHA functional class assessment, ECG and circulating biomarkers are more practical. Nevertheless, the entire battery of tests should be performed yearly in patients with diagnosed ATTR-CM, with some tests performed twice during this period. Attempts should be made to coordinate specialists to minimize the number of hospital visits.

Accurate baseline levels are crucial; this includes the initial disease staging and knowledge of relevant markers for early vs. late stage of ATTR-CM. Reproducibility of certain measures, such as NT-proBNP, echocardiography and CMR has not been demonstrated in ATTR-CM, so parameters that are evaluated over multiple timepoints may be more meaningful than those used at specific cut-off values.

The experts highlighted that ATTR-CM phenotype (ATTRv vs. ATTRwt) and disease stage may impact the feasibility or reliability of the measurements used to monitor cardiac disease progression in ATTR-CM patients, supporting the importance of a 

Physical frailty and biological age, and the patient's own perception of disease worsening were generally not considered to influence the measurement tools. However, it was noted that elderly people frequently present with degenerative conduction diseases such as AV blocks (even in the absence of amyloidosis), which may complicate the interpretation of ECG findings.

An additional factor when considering meaningful change is the potential delay in treatment effect, and this should be taken into account whilst the disease stabilizes, particularly during the initial 6-12-month interval after starting treatment. This recommendation underpins the importance of robust measures to discern between cardiac remodelling or lack of efficacy in patients with advanced-stage disease, and it is believed that imaging parameters may play a key role in this distinction in the future. Currently, long-term data in treated ATTR-CM patients are lacking, so clear endpoints indicating disease progression or stability are unknown. Findings from phase 3 trials, such as the ATTR-ACT study, may provide relevant endpoints for treatment goals 13 and long-term data will also inform these decisions. The panel stressed that where these tools indicate ATTR-CM progression, measurements should not be interpreted as a recommendation to discontinue disease-modifying therapies.

To improve the management of patients with ATTR-CM, several studies assessing the relationship between patient outcome and progression help inform therapeutic decisions (Table 3) . Therefore, a set of parameters measuring physical function, biomarkers and imaging should be categorized into different ATTR-CM disease stages based on their relationship with progression and survival. Data from placebo arms of RCTs will provide an opportunity to observe progressive changes in cardiac geometry and will allow a comparison of progressive changes in treated vs. untreated ATTR-CM patients. 10 Another area of future research includes the validation of systemic ATTR biomarkers for the production and plasma concentration of circulating TTR and unstable TTR. These include kinetic and peptide biomarkers that selectively bind to misfolded pathogenic oligomers in the serum; however, these are in the early stages of clinical investigation. 62 The experts propose that long-term studies in patients with ATTR-CM should explore global measurements of frailty, stratifying patients by age, severity and ATTR-CM phenotype. Ideally, multidimensional assessment of frailty should be incorporated into ongoing holistic assessment of ATTR-CM patients, but further studies are required to understand better how different frailty phenotypes influence disease progression. In a similar vein, owing to the typical late-stage diagnosis, the data to support these measures of progression tend to be from older patients; it is hoped that with improved diagnosis and awareness, disease progression in early-stage patients can be characterized. Assessment of cardiac progression in mixed ATTRv phenotype should be part of a multisystemic evaluation, in which progression, stability or improvement of other involved organs (i.e. peripheral neuropathy, kidneys and the autonomic system) should also be considered as they contribute to the overall interpretation of the disease course. 63 This report also highlights the need for more research validating imaging parameters for ATTR-CM progression, including CMR, T1 mapping and ECV changes, and radionuclide imaging with SPECT and PET. A recognized limitation of the study was the lack of patient engagement for selecting relevant endpoints. It is hoped that future studies that focus on such endpoints, including patient surveys and patient-reported outcomes studies will gain perspective on what matters most to patients.

A minimum set of parameters should be used to detect disease progression in patients diagnosed with ATTR-CM and these measures should be performed in a relatively short timeframe (6-12 months) after diagnosis or commencing treatment for ATTR-CM. Parameters should include the following: Upcoming data on non-treated patients will help to elucidate, refine and define these measurements. consultancy and speaker honoraria from Pfizer and Alnylam. P.M.E. has received consultancy fees from Pfizer, Alnylam, MyoKardia and Sanofi Genzyme and an unrestricted educational grant from Pfizer.

Flow chart of consensus process Appendix 2 25 clinical features identified by the experts in survey 1 6 -min walk test/functional capacity Body composition monitoring Conduction abnormalities Cardiovascular-related hospitalizations/hospitalization for heart failure E/e ′ Estimated glomerular filtration rate Extracellular volume Left ventricular global longitudinal strain High-sensitivity troponin T Interventricular septum thickness Liver congestion (laboratory evaluation) Left ventricular ejection fraction Left ventricular mass and wall thickness Mean pulmonary arterial pressure Native T1 times Need for intravenous therapy to treat heart failure (emergency department -no hospitalization) NT-proBNP NYHA class/heart failure class Peripheral oedema/need for diuretics to treat heart 

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Medical writing and editorial assistance were provided by Aisling Koning and Kyle Lambe of Synergy Medical Communications, London, UK, and was supported by Pfizer.

Editorial support for the development of this manuscript was funded by Pfizer. Authors were not paid for their work developing the manuscript and the views and opinions expressed are solely those of the authors. Conflict of interest: P.G.-P. has received speaking fees from Pfizer, Eidos, Alnylam and Akcea; consulting fees from Pfizer, Eidos, Neuroinmmune, Alnylam, AstraZeneca, Prothena and Akcea; research/educational support to his institution from Pfizer, Eidos and Alnylam; and grant support by the Instituto de Salud Carlos III (PI20/01379). F.B. has received personal fees from Pfizer. D.B. has received consultancy fees from Pfizer, Amgen, Boehringer Ingelheim and Novartis; speaker fees from Pfizer; and institutional funding for clinical trials from Amgen, Boehringer Ingelheim and Novartis. T.D. has received a grant and personal fees from Pfizer. F.D. received speaker as well as consulting fees and congress support from Bayer, Novartis, AOP, Alnylam, and Pfizer; and institutional research funding from Pfizer. S.D. has received research grants from Pfizer and GE Healthcare; and consultant fees from Pfizer and GE Healthcare. J.N.-N. has received institutional funding for clinical trials from Pfizer, Akcea and Eidos; educational grants from Pfizer; and consultancy fees from Pfizer, Eidos, Akcea, and Alnylam. L.O. has received personal consultancy and speaker honoraria from Pfizer, Alnylam and Akcea. C.R. discloses no conflict of interest. Y.S. has received grants,