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ObjectivesIn AL amyloidosis, organ response assessment is based on surrogates (eg, cardiac biomarkers). An objective functional test, such as the 6 min walk test (6MWT), capturing overall clinical improvement, is required. We aimed to evaluate the prognostic impact of the 6MWT at baseline and change following chemotherapy.MethodsThis study evaluated the outcomes of patients who enrolled in a prospective observational study at the UK National Amyloidosis Centre (2012–2017). Patients underwent comprehensive assessments inclusive of blood testing, echocardiogram and 6MWT at baseline and annually thereafter.ResultsIn total, 799 patients were included within the study. Median baseline 6 min walk distance (6MWD) was 362 m (IQR: 231 m). 6MWD progressively decreased with worsening cardiac disease stage (458 m, 404 m, 331 m and 168 m for cardiac Mayo stages I, II, IIIa and IIIb, respectively (pConclusionThe 6MWT is prognostic in AL amyloidosis. A baseline distance of ≥350 m independently predicts better survival. These data suggest that 6MWT has utility in AL amyloidosis for baseline prognosis and assessing response.

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent.

ObjectivesWild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage, the clinical course varies substantially between individuals. There are currently no established measures of rate of disease progression. Through systematic analysis of functional, biochemical and echocardiographic disease-related variables we aimed to identify prognostic markers of disease progression in wtATTR-CM.MethodsThis is a retrospective observational study of 432 patients with wtATTR-CM diagnosed at the UK NAC, none of whom received disease-modifying therapy. The association between mortality from the 12-month timepoint and change from diagnosis to 12 months in a variety of disease-related variables was explored using Cox regression.ResultsChange in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) at 12 months from diagnosis was the strongest predictor of ongoing mortality and was independent of both change in other disease-related variables (HR 1.04 per 500 ng/L increase (95% CI 1.01 to 1.07); p=0.003) and a range of known prognostic variables at the time of diagnosis (HR 1.07 per 500 ng/L increase (95% CI 1.02 to 1.13); p=0.007). An increase in NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L during the first year of follow-up occurred in 45%, 35% and 16% of patients, respectively.ConclusionChange in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.

BackgroundThe global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient’s preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis.Main bodyATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19.ConclusionPatients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.

Objectives The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. Methods Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001 and 2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity-matched scoring approach. Results A total of 136 propensity score-matched patients were included (ASCT n = 68, bortezomib n = 68). There was no significant difference in overall survival at two years (P = .908, HR: 0.95, CI: 0.41-2.20). For ASCT vs bortezomib: overall haematological response rate at 6 months was 90.6% vs 92.5%; organ response at 12 months: cardiac (70.0% vs 54%, P > .999), renal (74% vs 24%, P = .463) liver (21% vs 22%, P = .048); median progression-free survival (50 vs 42 months P = .058, HR: 0.61, CI: 0.37-1.02) and time to next treatment (68 vs 45 months, P = .145, HR: 0.61, CI: 0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs 23, Chi-squared P = .004) and 48 months (57 vs 41, Chi-squared P = .004). Conclusions This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed.

The purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV) mapping in cases of transthyretin cardiomyopathy (ATTR-CM).Administration of patisiran, a TTR-specific small interfering RNA (siRNA), has been shown to benefit neuropathy in patients with hereditary ATTR amyloidosis, but its effect on ATTR-CM remains uncertain.Patisiran was administered to 16 patients with hereditary ATTR-CM who underwent assessment protocols at the UK National Amyloidosis Centre. Twelve of those patients concomitantly received diflunisal as a "TTR-stabilizing" drug. Patients underwent serial monitoring using cardiac magnetic resonance, echocardiography, cardiac biomarkers, bone scintigraphy, and 6-min walk tests (6MWTs). Findings of amyloid types and extracellular volumes were compared with those of 16 patients who were retrospectively matched based on cardiac magnetic resonance results.Patisiran was well tolerated. Median serum TTR knockdown among treated patients was 86% (interquartile range [IQR]: 82% to 90%). A total of 82% of cases showed80% knockdown. Patisiran therapy was typically associated with a reduction in ECV (adjusted mean difference between groups: -6.2% [95% confidence interval [CI]: -9.5% to -3.0%]; p = 0.001) accompanied by a fall in N-terminal pro-B-type natriuretic peptide concentrations (adjusted mean difference between groups: -1,342 ng/l [95% CI: -2,364 to -322]; p = 0.012); an increase in 6MWT distances (adjusted mean differences between groups: 169 m [95% CI: 57 to 2,80]; p = 0.004) after 12 months of therapy; and a median reduction in cardiac uptake by bone scintigraphy of 19.6% (IQR: 9.8% to 27.1%).Reductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.

Hereditary apolipoprotein A-I (AApoAI) amyloidosis is a rare heterogeneous disease with variable age of onset and organ involvement. There are few series detailing the natural history and outcomes of solid organ transplantation across a range of causative APOA1 gene mutations.We identified all patients with AApoAI amyloidosis who presented to the National Amyloidosis Centre (NAC) between 1986 and 2019.In total, 57 patients with 14 different APOA1 mutations were identified including 18 patients who underwent renal transplantation (5 combined liver-kidney (LKT) and 2 combined heart-kidney (HKT) transplants). Median age of presentation was 43 years and median time from presentation to referral was 3 (0-31 years). Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively. Renal amyloidosis was universal in association with the most commonly identified variant (Gly26Arg,AApoAI amyloidosis is a slowly progressive disease that is challenging to diagnose. The outcomes of transplantation are encouraging and graft survival is excellent.

The heart is frequently involved in systemic amyloidosis. More than 30 precursor proteins have been identified that can form amyloid fibrils in vivo, and determination of the fibril type by immunohistochemistry, proteomics and genetic sequencing is crucial as this guides therapy. Most cases of cardiac amyloidosis are either transthyretin (TTR) type, which can be acquired, especially in men at a later age (wild type) or hereditarily at a younger age, or monoclonal immunoglobulin light chain (AL) type amyloidosis, which is acquired and most often occurs in middle age. Cardiac involvement occurs in about 50% of patients with AL amyloidosis and is the major determinant of prognosis in that condition. There are now several imaging modalities available to allow accurate evaluation of cardiac amyloidosis. The variable organ involvement often leads to delays in diagnosis. Improving awareness of amyloidosis is essential if patients are to be diagnosed early to impact on survival and quality of life.

Aims Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course. Methods and results We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P

Background: Daratumumab is a monoclonal antibody, which targets CD38; an antigen expressed on malignant plasma cells in AL amyloidosis thus providing a rationale for its use.Method: Patients treated with daratumumab monotherapy (2016-2019) for relapsed/refractory systemic AL amyloidosis were identified from the database at the UK National Amyloidosis Centre.Results: Of 50 evaluable patients, haematological responses at 3 months were: CR - 19 (38%), VGPR - 14 (28%), PR - 9 (18%) and no response - 8 (16%). Median time to response was 1 (1-6) month. Of assessable patients, cardiac, renal and hepatic responses were seen in 43.8%, 25.0% and 0% of patients whilst progression occurred in 25.0%, 12.5% and 37.5% respectively. Patients achieving a CR had longer median OS (not reached vs. 22.7 months [95% CI 17.0-28.4 months]) (p = .036). Furthermore, patients achieving a rapid response (at 1 month) had a longer median PFS (not reached vs. 9 months [95% CI 5.8-12.2 months]) (p = .013).Conclusion: Daratumumab monotherapy is effective in multiply-relapsed systemic AL amyloidosis and should be considered, if available, in patients who have not received prior daratumumab therapy. Responses are achieved rapidly and overall response rate was 84%. CR predicts overall survival whilst speed of response is predictive of a longer PFS.

Background Development of amyloidosis post solid-organ transplantation has not been reported, although plasma cell neoplasms are a rare form of posttransplant lymphoproliferative disorder, which could be complicated by light chain amyloidosis (AL) amyloidosis. Methods We searched our database of 5112 patients seen between 1994 and 2018 with a diagnosis of amyloidosis post solid-organ transplant. Patients were excluded if the amyloid diagnosis preceded the transplant date. The indication and type of organ transplant were recorded in addition to the amyloidosis type, organs involved, treatment given, and survival. Results Thirty patients were identified. The median age at diagnosis with amyloidosis was 52 years (range 33-77). The median time from transplantation to diagnosis was 10.5 years (0.58-36). The grafts were kidney (N = 25, 83.3%), liver (N = 2, 6.7%), heart (N = 2, 6.7%), and combined heart, lung, and kidney (N = 1, 3.3%). The type of amyloidosis was systemic AL (N = 14, 47%), serum amyloid A amyloidosis (AA) (N = 11, 37%), localized AL (N = 3, 10%), wild-type transthyretin amyloidosis (ATTR) (N = 1, 3.3%), and amyloid of uncertain type (N = 1, 3.3%). Renal graft dysfunction was seen in 11 of 25 (44%) cases. Median graft survival was 185 months (96-269), and median survival from diagnosis with amyloidosis was 45 months (2-89); median survival by amyloidosis type was localized AL: 64 months (20-67), systemic AL: 23.5 months (0-95), ATTR amyloidosis: 17 months, and AA, 15 months (0-77). Conclusions This series is the first description of amyloidosis post solid-organ transplant; 30 cases among 5112 amyloid patients >24 years suggests that amyloidosis may occur post solid-organ transplantation with an overall poor survival.

With improving outcomes in amyloid light-chain (AL) amyloidosis, there is a need to study novel agents in this setting. We report outcomes of 40 patients with relapsed AL amyloidosis treated with ixazomib + lenalidomide + dexamethasone (IRd). Haematological responses were assessed on an intention-to-treat basis at three months: complete response (CR) - 8 (20·5%), very good partial response (VGPR) - 8 (20·5%), partial response (PR) - 7 (17·9%) and no response (NR) - 16 (41·0%). One patient had missing data. Six patients subsequently improved response. Best responses were: CR - 10 (25·6%), VGPR - 8 (20·5%), PR - 7 (17·9%), NR - 14 (35·9%). Cardiac and renal organ responses occurred in 5·6% and 13·3% respectively. Median progession-free survival (PFS) was 17·0 months (95% CI 7·3-20·7 months), improving to 28·8 months (95% CI 20·6-37·0 months) in those achieving CR/VGPR. Median overall survival was 29·1 months (95% CI 24-33 months). Serious adverse events were seen in 14 (35·0%) patients inclusive of 15 admissions due to: infection (6/15, 40·0%), fluid overload (5/15, 33·3%), cardiac arrhythmia (2/15, 13·3%), renal dysfunction (1/15, 6·6%) and anaemia (1/15, 6·6%). In summary, IRd is an oral treatment option with a manageable toxicity profile leading to deep responses in 47% of patients with relapsed AL amyloidosis.

Objectives The aim of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of patients with ATTR-CM; and to study the association with mortality. Background The clinical significance of LA involvement in ATTR-CM is of great clinical interest. Methods Congo red staining and immunohistochemistry was performed to assess the presence, type, and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle tracking was used to assess LA reservoir, conduit, contractile function, and stiffness in 906 patients with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other). Results There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, vessels remodeling, capillary disruption, and subendocardial fibrosis. Echo speckle tracking in 906 patients with ATTR-CM demonstrated increased atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]) that remained independently associated with prognosis after adjusting for known predictors (lnLA stiff: HR: 1.23; 95% CI: 1.03-1.49; P = 0.029). There was substantial impairment of the 3 phasic functional atrial components (reservoir 8.86% [5.94%-12.97%]; conduit 6.5% [4.53%-9.28%]; contraction function 4.0% [2.29%-6.56%]). Atrial contraction was absent in 22.1% of patients whose electrocardiograms showed sinus rhythm (SR) “atrial electromechanical dissociation” (AEMD). AEMD was associated with poorer prognosis compared with patients with SR and effective mechanical contraction (P = 0.0018). AEMD conferred a similar prognosis to patients in atrial fibrillation. Conclusions The phenotype of ATTR-CM includes significant infiltration of the atrial walls, with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis., Central Illustration

Aims Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized. Methods and results A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of 100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23–20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297). Conclusion Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.

Background Hyperthyroidism is commonly associated with adverse cardiovascular effects, including tachydysrhythmia, heart failure, and hypertension, although the association between hyperthyroidism and myopericarditis is restricted to a small number of case reports. Case summary A 45-year-old Caucasian male with no past medical history was admitted with chest pain. The electrocardiogram demonstrated diffuse ST-segment elevation, the troponin T rose, and he was diagnosed with myopericarditis. He was noted to have markedly deranged thyroid function tests and a diagnosis of hyperthyroidism secondary to Graves’ disease was made. He was treated with Bisoprolol, Carbimazole, Prednisolone, Ibuprofen, and Colchicine, his symptoms resolved rapidly and he was discharged. Five weeks later he re-presented with similar symptoms and recurrent pericarditis was diagnosed. His symptoms settled with a repeat course of steroids. Discussion We hypothesize that there may be an underappreciated link between hyperthyroidism and myopericarditis. Potential pathophysiological mechanisms include viral infection, autoimmunity, or changes in myocardial fat metabolism. Suggested management consists of a combination of current guidelines for the treatment of hyperthyroidism and pericardial disease, with attention to certain disease–drug interactions. Further research is required to evaluate the true incidence of hyperthyroidism-associated myopericarditis, elucidate its pathophysiology and instruct management.

Bortezomib is a standard therapy in light-chain amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum-free light chains (dFLC)10 mg/L (low dFLC response) predicts survival in AL patients with low presenting dFLC (20-50 mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore the impact of posttreatment dFLC10 mg/L ("stringent dFLC response"). A total of 915 newly diagnosed AL patients treated with bortezomib and assessed at our center were included. Hematologic responses, 6-month dFLC, organ responses, overall survival (OS), and time-to-next-treatment (TNT) (excluded patients who died without starting second-line treatment) were evaluated. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low dFLC response and with a stringent dFLC response, dFLC 10-40 mg/L, and dFLC40 mg/L was 30%, 22%, and 48%, respectively. Median OS was 72 months. A total of 289 patients died without progressing to second-line treatment. Median TNT was not reached, and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than did those with lesser responses. A total of 72% of CR patients did not progress to further treatment at 3 years compared with 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared with lesser responses (45%; P = .005). Upfront bortezomib confers durable hematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.

The mechanics of the mitral valve (MV) are the result of the interaction of different anatomical structures complexly arranged within the left heart (LH), with the blood flow. MV structure abnormalities might cause valve regurgitation which in turn can lead to heart failure. Patient-specific computational models of the MV could provide a personalised understanding of MV mechanics, dysfunctions and possible interventions. In this study, we propose a semi-automatic pipeline for MV modelling based on the integration of state-of-the-art medical imaging, i.e. cardiac magnetic resonance (CMR) and 3D transoesophageal-echocardiogram (TOE) with fluid-structure interaction (FSI) simulations. An FSI model of a patient with MV regurgitation was implemented using the finite element (FE) method and smoothed particle hydrodynamics (SPH). Our study showed the feasibility of combining image information and computer simulations to reproduce patient-specific MV mechanics as seen on medical images, and the potential for efficient in-silico studies of MV disease, personalised treatments and device design.

Autologous stem cell transplantation (ASCT) is considered to be the best method to achieve deep haematological/organ responses and improve survival in selected patients with AL amyloidosis. This field has been led by US centres and is less utilised in Europe. The introduction of effective chemotherapy agents for AL prompted us to re-evaluate UK outcomes of ASCT in affected patients. A total of 264 AL amyloidosis patients treated with an ASCT between 1994 and 2018 were identified. Patient baseline characteristics, transplant-related mortality (TRM) and overall survival (OS) were analysed. The median OS post-ASCT was 87 months [95% confidence interval (CI): 77-106 months]. The median time from ASCT to next treatment was 48 months (95% CI: 29-55 months). A haematological response was achieved in 94·8% of patients and was a strong predictor of time to next treatment [P < 0·0001, hazard ratio (HR) = 1·75, 95% CI = 1·35-2·28] and OS (P = 0·007, HR = 1·91, 95% CI = 1·19-3·07). Organ response was: cardiac (n = 28, 60·9%), renal (n = 101, 76%) and liver (n = 7, 13·5%). Overall TRM was 8·7%, with a significant reduction over time (1994-2000: 18·8%; 2001-2006: 13·6%; 2007-2012: 6·2%; 2013-2018: 1·1%). In conclusion, ASCT is significantly safer and remains a highly effective treatment with excellent long-term survival; it should be more widely considered as a treatment option for systemic AL amyloidosis.

Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. Methods: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V122I variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. Results: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9–27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P P P Conclusions: ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.

Here we describe a patient with genetically confirmed ATTR, a family history of the disease and histological confirmation following carpal tunnel release surgery but no other manifestations. The first major neurological or systemic manifestation was cauda equina syndrome with ATTR deposits contributing to lumbar spinal stenosis. Recent gene therapy trials showed improvement in the neuropathy in TTR amyloidosis. This case highlights the need for awareness of the heterogeneous neurological phenotype seen in ATTR to aid earlier diagnosis especially now that disease modifying therapies are available.

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.

Renal risk stratification in systemic immunoglobulin light-chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein 4 (uRBP), a low molecular weight tubular protein and highly sensitive marker of PTD, was prospectively measured in 285 newly diagnosed, untreated patients with systemic AL amyloidosis between August 2017 to August 2018. At diagnosis, the uRBP/creatinine ratio (uRBPCR) correlated with serum creatinine (r = 0·618, P 30 ml/min/1.73 m2 [HR 4·11, (95% CI 1·45-11·65); P = 0·008] and those who failed to achieve a deep haematological response to chemotherapy within 3 months of diagnosis [HR 6·72, (95% CI 1·83-24·74); P = 0·004], and also predicted renal progression [HR 1·91, (95% CI 1·18-3·07); P = 0·008]. Elevated uRBPCR indicates PTD and predicts renal outcomes independently of eGFR, uPCR and clonal response in systemic AL amyloidosis. The role of uRBPCR as a novel prognostic biomarker merits further study, particularly in monoclonal gammopathies of renal significance.

Background: Systemic amyloidosis is characterized by amyloid deposition that can involve virtually any organ. Splenic and hepatic amyloidosis occurs in certain types, in some patients but not others, and may influence prognosis and treatment. SAP (serum amyloid P component) scintigraphy is uniquely able to identify and quantify amyloid in the liver and spleen, thus informing clinical management, but it is only available in 2 centers globally. The aims of this study were to examine the potential for extracellular volume (ECV) mapping performed during routine cardiac magnetic resonance to: (1) detect amyloid in the liver and spleen and (2) estimate amyloid load in these sites using SAP scintigraphy as the reference standard. Methods: Five hundred thirty-three patients referred to the National Amyloidosis Centre, London, between 2015 and 2017 with suspected systemic amyloidosis who underwent SAP scintigraphy and cardiac magnetic resonance with T1 mapping were studied. Results: The diagnostic performance of ECV to detect splenic and hepatic amyloidosis was high for both organs (liver: area under the curve, −0.917 [95% CI, 0.880–0.954]; liver ECV cutoff, 0.395; sensitivity, 90.7%; specificity, 77.7%; P P P P P P Conclusions: Our study demonstrates that ECV measurements obtained during routine cardiac magnetic resonance scans in patients with suspected amyloidosis can identify and measure the magnitude of amyloid infiltration in the liver and spleen, providing important clues to amyloid type and offering a noninvasive measure of visceral amyloid burden that can help guide and track treatment.

Aims Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD scintigraphy) is recognized as highly accurate for the non-invasive diagnosis of transthyretin (ATTR) cardiac amyloidosis (CA). A proportion of patients with immunoglobulin light chain (AL) CA have also been reported to show cardiac 99mTc-DPD uptake. Herein, we assessed the frequency and degree of cardiac 99mTc-DPD uptake and its clinical significance among patients with AL CA. Methods and results Between 2010 and 2017, 292 consecutive patients with AL CA underwent 99mTc-DPD scintigraphy and were included in this study: 114 (39%) had cardiac 99mTc-DPD uptake: grade 1 in 75%, grade 2 in 17%, and grade 3 in 8% of cases. Patients with cardiac 99mTc-DPD uptake had poorer cardiac systolic function and higher N-terminal pro-brain natriuretic peptide. No differences were noted in cardiac magnetic resonance parameters between patients with and without cardiac 99mTc-DPD uptake (N = 19 and 42, respectively). Patients with cardiac 99mTc-DPD uptake showed a trend to worse survival than those with no uptake (log-rank P = 0.056). Among 22 patients who underwent serial 99mTc-DPD scintigraphy, 5 (23%) showed reduction in the grade of cardiac uptake. Conclusions In this large cohort of patients with AL CA, 99mTc-DPD scintigraphy ∼40% of cases showed cardiac uptake, including grade 2–3 in 10% of all patients (25% of those with cardiac 99mTc-DPD uptake). Cardiac 99mTc-DPD uptake was associated with poorer cardiac function and outcomes. These data highlight the critical importance of ruling out AL amyloidosis in all patients with cardiac 99mTc-DPD uptake to ensure such patients are not assumed to have ATTR CA.

Background Left atrial (LA) involvement in cardiac ATTR amyloidosis (ATTR-CM) has never being explored. The aim of the study is to characterize the spectrum of changes in LA structure in ATTR-CM, the functional consequences on LA mechanics and the association with mortality. Methods We studied 936 patients with ATTR-CM who underwent prospective protocolized evaluations comprising ECG, full echocardiographic assessment, 6MWT, blood biomarkers sampling and survival assessment between 2000 and 2019. Reservoir (LAr), conduit (LAcd) and booster (LAcont) function were assessed according to current guidelines. LA stiffness (LAstiff) was estimated as the ratio between E/e' and LAr. The presence and extent of amyloid infiltration was assessed in two autopsied hearts from patients ATTR-CM with congo red staining and TTR antibodies. Results 936 patients with ATTR-CM were included, 567 with wtATTR-CM and 346 with hATTR-CM, of whom 246 had the V122I variant and 100 the T60A variant. LA indexed area was similar across the 3 genotypes, whilst LAr, LAcd and LAcont were significantly reduced in V122I patients compared to Wt and T60A patients (LAr: 10.4±6.4 vs 12.8±8.5 vs 8.59±5.7%, p Conclusions ATTR-CM is characterized by primary infiltration of the atrial walls with progressive loss of atrial function and increased stiffness. LA stiffness is a strong independent predictor of mortality after adjusting for known predictors. Atrial electro-mechanical dissociation emerged as a distinctive functional phenotype identifying patients in SR with worse prognosis. Figure 1 Funding Acknowledgement Type of funding source: None

Aims Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). We sought to evaluate the utility of LS% in a prospectively observed series of patients. Methods and results A total of 915 serial newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included. A total of 628/915 (68.6%) patients had cardiac involvement. The LS% worsened with advancing cardiac stage with mean −21.1%, −17.1%, −12.9%, and −12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤−16.2%: 80 months, −16.1% to −12.2%: 36 [95% confidence interval (CI) 20.9–51.1] months, −12.1% to −9.1%: 22 (95% CI 9.1–34.9) months, and ≥−9.0%: 5 (95% CI 3.2–6.8) months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response (CR) (median improvement from −13.8% to −14.9% in those with CR and difference between involved and uninvolved light chain Conclusion Baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy in cardiac AL amyloidosis, respectively.

INTRODUCTION Systemic amyloidosis is a histological diagnosis, often achieved via critical organ biopsy. Screening biopsies represent a low-risk approach to diagnosis. OBJECTIVES AND METHODS All patients with systemic AL and ATTR amyloidosis who underwent abdominal fat aspiration (AFA) and either a bone marrow (BM) or gastrointestinal (GI) biopsy at the UK National Amyloidosis Centre (2006-2019) were identified. We sought to determine diagnostic sensitivity in relation to whole body amyloid burden, amyloid type and organ involvement. RESULTS Diagnostic sensitivity established in 471 patients with AL (n = 321) and ATTR (n = 150) amyloidosis, respectively, was 73.2% and 27.3% for AFA (P

Background and purpose: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. Methods: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. Results: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. Conclusion: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed. info:eu-repo/semantics/publishedVersion

High-dose melphalan with autologous stem cell transplantation (ASCT) can induce durable haematological and organ responses in systemic AL amyloidosis (AL). Stringent selection criteria have improved safety of ASCT in AL but most patients are transplant-ineligible. We report our experience of deferred ASCT in AL patients who were transplant-ineligible at presentation but had improvements in organ function after induction chemotherapy, enabling them to undergo ASCT. Twenty-two AL patients underwent deferred ASCT from 2011 to 2017. All had serial organ function and clonal response assessment. Organ involvement and responses were defined by amyloidosis consensus criteria. All patients were transplant-ineligible at presentation, predominantly due to advanced cardiac involvement. All received bortezomib-based therapy, with 100% haematologic response (86% complete response (CR)/very good partial response (VGPR)), enabling reversal of ASCT exclusion criteria. Patients underwent deferred ASCT for haematologic progression (45%) or consolidation (55%). There was no transplant-related mortality. Haematologic responses post-ASCT: CR 50%, VGPR 27%, PR 18%, non-response 5%. In all, 85.7% achieved cardiac responses. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 54 months. This selected cohort achieved excellent haematologic responses, organ responses, PFS and OS with deferred ASCT. If larger studies confirm these findings, this may widen the applicability of ASCT in AL.

18F-florbetapir is a promising tracer in amyloidosis. This study evaluates its use in patients with systemic AL amyloidosis (AL) before and after treatment as well as its serial utility in monitori...

TO THE EDITOR: Systemic amyloid light-chain amyloidosis (AL) is characterized by deposition of misfolded immunoglobulin light chains within organs. AL with an immunoglobulin M (IgM) monoclonal protein (IgM-AL) accounts for 5% to 7% of AL and exhibits more prevalent lymph node, neuropathic, and lung

Background Systemic Immunoglobulin light chain amyloidosis (AL) is a protein-misfolding disorder associated with an underlying monoclonal B-cell or plasma cell dyscrasia. There is little information on how response durability impacts outcomes. It is conceivable that early relapse may confer an adverse prognosis in AL, like in Myeloma. Here, we test the above hypothesis and analyse the factors affecting response durability in a cohort of AL patients treated with frontline Bortezomib. Methods All patients treated with frontline Bortezomib in 2010-2019 are included in the analysis. Patients with primary refractory disease, those with a continuing response but ≤ 24 months follow up, and those who received 2nd line therapy for reasons other than progression are excluded from the analysis. We defined early relapse (ER) as PFS ≤ 24 months. Results 560 patients are included in this analysis. 250 (44.6%) and 310 (55.4%) patients had ER and LR, respectively. The ER group had more advanced cardiac disease (p 20% (p=0.021), ≥ VGPR after 1st line (p 20%, and dFLC Conclusions In conclusion, these data identify a high-risk group of patients who relapse early and have a poorer survival (irrespective of their initial response). The depth of response to the initial treatment is a critical determinant of response durability. The early relapses should be considered for clinical trials that can identify treatments with the potential to overcome the high-risk biology of the disease.

Background Cardiac transthyretin amyloidosis (ATTR) is an increasingly recognized cause of heart failure. Cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) and T1 mapping, is emerging as a reference standard for diagnosis and characterization of cardiac amyloidosis. Objectives The authors used CMR with extracellular volume fraction (ECV) measurement to characterize cardiac involvement in relation to outcome in ATTR. Methods Subjects comprised 263 patients with cardiac ATTR corroborated by grade 2 to 3 99mTc-DPD (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid) cardiac uptake, 17 with suspected cardiac ATTR (grade 1 99mTc-DPD), and 12 asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations. Fifty patients with cardiac light-chain (AL) amyloidosis acted as disease comparators. Results Unlike cardiac AL amyloidosis, asymmetrical septal left ventricular hypertrophy (LVH) was present in 79% of patients with ATTR (70% sigmoid septum and 30% reverse septal contour), whereas symmetrical LVH was present in 18%, and 3% had no LVH. In patients with cardiac amyloidosis, the pattern of LGE was always typical for amyloidosis (29% subendocardial, 71% transmural), including right ventricular LGE (96%). During follow-up (19 ± 14 months), 65 patients died. ECV independently correlated with mortality and remained independent after adjustment for age, N-terminal pro-B-type natriuretic peptide, ejection fraction, E/E′, and left ventricular mass (hazard ratio: 1.164; 95% confidence interval: 1.066 to 1.271; p Conclusions Asymmetrical hypertrophy, traditionally associated with hypertrophic cardiomyopathy, was the commonest pattern of ventricular remodeling in ATTR. LGE imaging was typical in all patients with cardiac ATTR. ECV correlated with amyloid burden and was an independent prognostic factor for survival in this cohort of patients.

Introduction Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. Methods We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. Results The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. Conclusions Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.

Objectives Cardiac involvement and/or macroglossia with soft tissue deposits are risk factors for central sleep apnoea (CSA) and obstructive sleep apnoea (OSA), and common features of systemic AL amyloidosis. Little data exist on the occurrence of sleep-disordered breathing (SDB) or recurrent nocturnal hypoxia in amyloidosis, which this study sought to investigate. Methods A total of 72 consecutive patients with systemic amyloidosis (mean age 69 years and mean BMI 25) were evaluated for occurrence of SDB, by overnight continuous pulse oximetry, and completed Epworth Sleepiness Score (ESS) and STOPBANG questionnaires. Patients included: AL cardiac (AL-C), AL macroglossia (AL-M), AL both (AL-CM) and transthyretin (ATTR). Results Mean overnight oxygen saturations were 93% (SD ± 2, 95% CI 87–96) with abnormal oximetry (4% oxygen desaturation index (ODI) >5/hour): AC-C 84%, AL-M 57%, AL-CM 62% and ATTR 47%. NYHA class directly correlated with a higher 4% ODI, NYHA class I vs 3, ( p = 0.01). Two-thirds of patients had STOPBANG scores >3 and abnormally high ESS scores (>10) were seen in up to 30% of patients. Conclusion Recurrent nocturnal hypoxaemia, suggestive of sleep-disordered breathing, is frequent in systemic AL amyloidosis. The higher incidence in cardiac amyloidosis highlights CSA and recurrent hypoxia as possible mechanisms for morbidity/mortality in these cases. A detailed polysomnography study is planned to clarify and further investigate these findings.

Aims Congo red staining of an endomyocardial biopsy is the diagnostic gold-standard in suspected cardiac amyloidosis (CA), but the procedure is associated with the risk, albeit small, of serious complications, and delay in diagnosis due to the requirement for technical expertise. In contrast, abdominal fat pad fine needle aspiration (FPFNA) is a simple, safe and well-established procedure in systemic amyloidosis, but its diagnostic sensitivity in patients with suspected CA remains unclear. Methods and results We assessed the diagnostic sensitivity of FPFNA in 600 consecutive patients diagnosed with CA [216 AL amyloidosis, 113 hereditary transthyretin (ATTRm), and 271 wild-type transthyretin (ATTRwt) amyloidosis] at our Centre. Amyloid was detected on Congo red staining of FPFNAs in 181/216 (84%) patients with cardiac AL amyloidosis, including 100, 97, and 78% of those with a large, moderate, and small whole-body amyloid burden, respectively, as assessed by serum amyloid P (SAP) component scintigraphy (P < 0.001); the deposits were successfully typed as AL by immunohistochemistry in 102/216 (47%) cases. Amyloid was detected in FPFNAs of 51/113 (45%) patients with ATTRm CA, and only 42/271 (15%) cases with ATTRwt CA. Conclusions FPFNA has reasonable diagnostic sensitivity in cardiac AL amyloidosis, particularly in patients with a large whole-body amyloid burden. Although the diagnostic sensitivity of FPFNA is substantially lower in transthyretin CA, particularly ATTRwt, it may nevertheless sometimes obviate the need for endomyocardial biopsy.

AIMS: High-grade (Perugini grade 2 or 3) cardiac uptake on bone scintigraphy with 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has lately been confirmed to have high diagnostic sensitivity and specificity for cardiac transthyretin (ATTR) amyloidosis. We sought to determine whether patient stratification by Perugini grade on 99mTc-DPD scintigraphy has prognostic significance in ATTR amyloidosis. METHODS AND RESULTS: Patient survival from time of 99mTc-DPD scintigraphy was determined in 602 patients with ATTR amyloidosis, including 377 with wild-type ATTR (ATTRwt) and 225 with mutant ATTR (ATTRm) amyloidosis. Patients were stratified according to Perugini grade (0-3) on 99mTc-DPD scan. The prognostic significance of additional patient and disease-related factors at baseline were determined. In the whole cohort, the finding of a Perugini grade 0 99mTc-DPD scan (n = 28) was invariably associated with absence of cardiac amyloid according to consensus criteria as well as significantly better patient survival compared to a Perugini grade 1 (n = 28), 2 (n = 436) or 3 (n = 110) 99mTc-DPD scan (P

Background The six-minute walk test (6MWT) is an easy-to-implement objective measure of functional capacity. This standardised reproducible measure of individual function may have value in systemic AL amyloidosis to provide an additional objective measure of fitness for chemotherapy, impact of chemotherapy and, within the clinical trial setting, both as a potential clinical endpoint and exclusion criteria. We aim to validate its prognostic value in AL amyloidosis. Methods All patients from a prospective observational study of newly diagnosed AL amyloidosis, (ALchemy) over a 5-year period, were studied. Six-minute walk testing was performed at baseline and 6, 12, 18, 24, 36 and 48-month follow up. Both the median 6MWT and percentage predicted for age, sex, height and weight were analysed. Results In total, 799 evaluable patients were included of whom 564 (70.6%) had cardiac involvement. Baseline 6MWT distance was 418.5 metres (m) / 80.5% predicted, and diminished with increasing cardiac Mayo stage (p Patients were followed up for a median of 32 (1-90) months following diagnosis. Median overall survival (OS) was 70.0 (56.8-83.2) months. The median OS of patients achieving ≥300m on baseline 6MWT was not reached whilst those achieving The 6MWT fell significantly by 6 months (391.0m/73.5%, p=0.0002) then rose again by 12 months (median 415.0m/78.0%, p=0.02). There was no significant change in 6MWT thereafter. When stratified by haematological response and censoring deaths before 12 months, only patients in a complete response (CR) improved at 12 months (431.0m/83.0% vs. 437.0m/85%, p=0.001) whilst those with a lesser haematological response got worse (Very good partial response [VGPR]: 403.5m/75.0% to 395.5m/76.5%, p=0.02; Partial Response [PR]: 413.0m/79.0% to 362.5m/74.0%, p=0.0007; Nil response [NR]: 437.0m/83.0% to 355.0m/70%, p=0.0002). A 33m improvement in 6MWT, a value reported to be clinically meaningful in cardiopulmonary disorders, was independent of haematological response in predicting survival (CR [reference], VGPR: HR 2.02 [1.08-3.80], p=0.03; PR: HR 3.51 [1.83-6.73], p Patients in whom 6MWT improved by ≥33m at 12 months survived longer although median OS was not reached in either category (p=0.01). In patients who achieved a baseline 6MWT of Conclusion The 6MWT is prognostic in AL amyloidosis at multiple time points and a baseline distance of ≥300m is independent of current Mayo stage criteria in predicting survival. Inability to undertake a 6MWT at baseline is an extremely poor prognostic indicator. At 12 months, improvement in 6MWT of ≥33m predicts survival independent of haematological response. The 6MWT is a useful prognostic indicator in systemic AL amyloidosis and could be used as an inclusion/exclusion criterion in the clinical trial setting. Disclosures Wechalekar: Celgene: Honoraria; Takeda: Honoraria, Other: Travel; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.

Systemic light-chain (AL) amyloidosis is characterized by interstitial deposition of aggregated misfolded monoclonal immunoglobulin light chains in the form of amyloid fibrils. Cardiac involvement is the main driver of prognosis. Brain natriuretic peptides and echocardiography are currently the

Aims Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis. Methods and results We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e’ were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001). Conclusion The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide 152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.