Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome. METHODS: Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality. RESULTS: Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; P<0.001), whereas Perugini grade was not associated with survival (P=0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; P<0.001), presence of the p.(V142I) TTR variant (HR, 1.42 [95% CI, 1.20-1.81]; P=0.004), National Amyloidosis Centre stage (each category, P<0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; P=0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; P=0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; P=0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; P<0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; P<0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM (P<0.001 and P=0.02, respectively). CONCLUSIONS: Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis.

Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis.

AIMS: To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease. METHODS AND RESULTS: A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM. CONCLUSION: The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.

Characteristics and natural history of early-stage cardiac transthyretin amyloidosis.

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 <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >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.

Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis.

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.

Natural History, Quality of Life, and Outcome in Cardiac Transthyretin 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 V1221 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<0.001) and had worse measures of cardiac disease ( P<0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P<0.001) in comparison with the other subgroups. 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.

Relative Contributions of Packaging Elements to the Thermal Hysteresis of a MEMS Pressure Sensor.

Piezoresistive silicon pressure sensor samples were thermally cycled after being consecutively packaged to three different levels. These started with the absolute minimum to allow measurement of the output and with each subsequent level incorporating additional packaging elements within the build. Fitting the data to a mathematical function was necessary both to correct for any testing uncertainties within the pressure and temperature controllers, and to enable the identification and quantification of any hysteresis. Without being subjected to any previous thermal preconditioning, the sensors were characterized over three different temperature ranges and for multiple cycles, in order to determine the relative contributions of each packaging level toward thermal hysteresis. After reaching a stabilised hysteretic behaviour, 88.5% of the thermal hysteresis was determined to be related to the bond pads and wire bonds, which is likely to be due to the large thermal mismatch between the silicon and bond pad metallisation. The fluid-fill and isolation membrane contributed just 7.2% of the total hysteresis and the remaining 4.3% was related to the adhesive used for attachment of the sensing element to the housing. This novel sequential packaging evaluation methodology is independent of sensor design and is useful in identifying those packaging elements contributing the most to hysteresis.

Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.

BACKGROUND: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. METHODS AND RESULTS: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100). CONCLUSIONS: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.

Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study.

PURPOSE: To investigate cardiac magnetic resonance (MR) imaging measurements of extracellular volume (ECV) and total cell volume in immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) in order to evaluate the amyloid and myocyte volumes. MATERIALS AND METHODS: All ethics were approved, and participants provided written informed consent. Of the 257 subjects who were recruited, 92 had AL (mean age, 62 years ± 10), 44 had mutant ATTR (mean age, 68 years ± 10), and 66 had wild-type ATTR (mean age, 75 years ± 7). In addition, eight healthy subjects with ATTR mutations (mean age, 47 years ± 6) and 47 healthy volunteers (mean age, 45 years ± 15) participated. All participants underwent equilibrium contrast material-enhanced cardiac MR imaging. ECV and total cell volume were measured in the heart. T test, χ(2), and one-way analysis of variance with posthoc Bonferroni correction were used. RESULTS: Both the left ventricular indexed mass and ECV were elevated in patients with amyloidosis. For left ventricular indexed mass, mean AL was 107 g/m(2) ± 30; mean mutant ATTR was 137 g/m(2) ± 29; and mean wild-type ATTR was 133 g/m(2) ± 27 versus 65 g/m(2) ± 15 in healthy subjects (P < .0001 for all measures). For ECV, mean AL was 0.54 ± 0.07, mean mutant ATTR was 0.60 ± 0.07, and mean wild-type ATTR was 0.57 ± 0.06 versus 0.27 ± 0.03 in healthy subjects (P < .0001 for all measures). Patients with ATTR had a higher total cell volume than did healthy subjects (mean, 53 mL/m(2) ± 12 vs 45 mL/m(2) ± 11; P = .001), but in patients with AL, total cell volume was normal (mean, 47 mL/m(2) ± 17 vs 45 mL/m(2) ± 11; P > .99). The result is that, in patients with AL, all of the increase in left ventricular indexed mass is extracellular volume, whereas in patients with ATTR, the increase is extracellular, with an additional 18% increase in the intracellular space. CONCLUSION: Quantification of ECV measures cardiac amyloid deposition in both types of amyloidosis and shows that amyloid deposition is more extensive in patients with ATTR than in those with AL; however, ATTR is associated with higher cell volume, which suggests concomitant cell hypertrophy.

Misdiagnosing renal amyloidosis as minimal change disease.

BACKGROUND: Minimal change disease (MCD) accounts for 10-15% of all adult nephrotic syndrome cases and requires normal renal histology by light microscopy and negative immunohistology. Foot process effacement on electron microscopy (EM) is typical. Renal amyloid deposits demonstrate pathognomonic green birefringence when viewed under cross-polarized light after staining tissue with Congo red (CR) and may reveal fibrils on EM. Late diagnosis and delayed treatment of renal amyloidosis negatively impact on renal and patient survival. METHODS: A retrospective analysis was performed on 2116 patients referred to the National Amyloidosis Centre between 2001 and 2013, in whom renal amyloidosis was confirmed histologically. Twenty-seven of these patients had renal histology initially interpreted to be MCD. RESULTS: Among 26 patients in whom biopsy specimens and/or reports were retrieved, the median age at MCD diagnosis was 62 years and presenting proteinuria averaged 7.8 g/24 h. The median time period between the two diagnoses was 241 days (range: 20-2632 days). MCD was diagnosed without CR in 17/26 (65%) biopsies, but all specimens contained amyloid on retrospective CR staining. MCD was diagnosed without EM in 17/26 (65%) cases and all of 10 such biopsies subsequently demonstrated fibrils. Sixteen patients were subjected to two or more renal biopsies when their proteinuria proved steroid refractory. CONCLUSION: This study highlights the need to stain renal biopsies from proteinuric adults with CR, examine them under cross-polarized light and perform EM wherever possible. If the suspicion of renal amyloidosis remains high, despite apparent negative histology, specimens should be reviewed at specialist centres before undertaking a second kidney biopsy.

The Role of Self-Assembled Monolayers in the Surface Modification and Interfacial Contact of Copper Fillers in Electrically Conductive Adhesives.

Printing of electrical circuits and interconnects using isotropic conductive adhesives (ICAs) is of great interest due to their low-temperature processing and compatibility with substrates for applications in sensors, healthcare, and flexible devices. As a lower cost alternative to silver (Ag), copper (Cu)-filled ICAs are desirable but limited by the formation of high-resistivity Cu surface oxides. To overcome this limitation, self-assembled monolayers (SAMs) of octadecanethiol (ODT) have been demonstrated to reduce the oxidation of micrometer-scale Cu powder particles for use in ICAs. However, the deposition and function of the SAM require further investigation, as described in this paper. As part of this work, the stages of the SAM deposition process, which included etching with hydrochloric acid to remove pre-existing oxides, were studied using X-ray photoelectron spectroscopy (XPS), which showed low levels of subsequent Cu oxidation when ODT coated. The treated Cu powders were combined with one- or two-part epoxy resins to make Cu-ICAs, and the effect of the Cu surface condition and weight loading on electrical conductivity was examined. When thermally cured in an inert argon atmosphere, ICAs filled with Cu protected by ODT achieved electrical conductivity up to 20 × 105 S·m-1, comparable to Ag-ICAs, and were used to make a functional circuit. To understand the function of the SAM in these Cu-ICAs, scanning and transmission electron microscopy were used to examine the internal micro- and nano-structures along with the elemental distribution at the interfaces within sections taken from cured samples. Sulfur (S), indicative of the ODT, was still detected at the internal polymer-metal interface after curing, and particle-to-particle contacts were also examined. XPS also identified S on the surface of cured Cu-ICAs even after thermal treatment. Based on the observations, electrical contact and conduction mechanisms for these Cu-filled ICAs are proposed and discussed.

Deep phenotyping of p.(V142I)-associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. A total of 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR-CM (ATTRv-CM); this equates to 1.6 million carriers in the United States. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM). METHODS AND RESULTS: A retrospective study of 413 patients with p.(V142I) ATTRv-CM who attended the UK National Amyloidosis Centre (NAC) was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance (CMR) imaging. A total of 413 patients with ATTRwt-CM, matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group. At time of diagnosis, patients with ATTRv-CM had significant functional impairment by New York Heart Association classification (NHYA class ≥ III; 38%) and 6-min walk test distance (median 276 m). Median 5-year survival in ATTRv-CM patients was 31 versus 59 months in matched patients with ATTRwt-CM (p < 0.001). Patients with ATTRv-CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of right ventricular dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM. CONCLUSION: p.(V142I)-ATTRv-CM has an aggressive phenotype characterized by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup.

Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR-CM. METHODS AND RESULTS: Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. The study population consisted of 2029 patients with ATTR-CM (median age 79 years at diagnosis, 13.5% females, 80.4% Caucasian). Variant ATTR-CM (ATTRv-CM) was diagnosed in 20.7% (n = 421) of the study population of whom 327 (77.7%) carried V122I, 47 (11.2%) T60A, 16 (3.8%) V30M and 31 (7.3%) other pathogenic TTR variants. During a median (range) follow-up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p < 0.001). Univariable and multivariable logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p < 0.001), female sex (OR 2.73, p < 0.001), Afro-Caribbean ethnicity (OR 65.5, p < 0.001), atrial fibrillation (OR 0.65, p = 0.015), ischaemic heart disease (OR 0.54, p = 0.007), peripheral polyneuropathy (OR 5.70, p < 0.001) and orthostatic hypotension (OR 6.29, p < 0.001) to be independently associated with ATTRv-CM. CONCLUSION: Up to 20.7% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age.

Tracking Multiorgan Treatment Response in Systemic AL-Amyloidosis With Cardiac Magnetic Resonance Derived Extracellular Volume Mapping.

BACKGROUND: Systemic light chain amyloidosis is a multisystem disorder that commonly involves the heart, liver, and spleen. Cardiac magnetic resonance with extracellular volume (ECV) mapping provides a surrogate measure of the myocardial, liver, and spleen amyloid burden. OBJECTIVES: The purpose of this study was to assess multiorgan response to treatment using ECV mapping, and assess the association between multiorgan treatment response and prognosis. METHODS: The authors identified 351 patients who underwent baseline serum amyloid-P-component (SAP) scintigraphy and cardiac magnetic resonance at diagnosis, of which 171 had follow-up imaging. RESULTS: At diagnosis, ECV mapping demonstrated that 304 (87%) had cardiac involvement, 114 (33%) significant hepatic involvement, and 147 (42%) significant splenic involvement. Baseline myocardial and liver ECV independently predict mortality (myocardial HR: 1.03 [95% CI: 1.01-1.06]; P = 0.009; liver HR: 1.03; [95% CI: 1.01-1.05]; P = 0.001). Liver and spleen ECV correlated with amyloid load assessed by SAP scintigraphy (R = 0.751; P < 0.001; R = 0.765; P < 0.001, respectively). Serial measurements demonstrated ECV correctly identified changes in liver and spleen amyloid load derived from SAP scintigraphy in 85% and 82% of cases, respectively. At 6 months, more patients with a good hematologic response had liver (30%) and spleen (36%) ECV regression than myocardial regression (5%). By 12 months, more patients with a good response demonstrated myocardial regression (heart 32%, liver 30%, spleen 36%). Myocardial regression was associated with reduced median N-terminal pro-brain natriuretic peptide (P < 0.001), and liver regression with reduced median alkaline phosphatase (P = 0.001). Changes in myocardial and liver ECV, 6 months after initiating chemotherapy, independently predict mortality (myocardial HR: 1.11 [95% CI: 1.02-1.20]; P = 0.011; liver HR: 1.07 [95% CI: 1.01-1.13]; P = 0.014). CONCLUSIONS: Multiorgan ECV quantification accurately tracks treatment response and demonstrates different rates of organ regression, with the liver and spleen regressing more rapidly than the heart. Baseline myocardial and liver ECV and changes at 6 months independently predict mortality, even after adjusting for traditional predictors of prognosis.

The role of serial 99mTc-DPD scintigraphy in monitoring cardiac transthyretin amyloidosis.

PURPOSE: Cardiac transthyretin amyloidosis is a usually fatal form of restrictive cardiomyopathy for which clinical trials of treatments are ongoing. It is anticipated that quantitative nuclear medicine scintigraphy, which is experiencing growing interest, will soon be used to evaluate treatment efficacy. We investigated its utility for monitoring changes in disease load over a significant time period. METHODS: Sixty-two treatment-naive patients underwent 99mTc-labelled 3,3-diphosphono-1,2propanodicarboxylic acid (99mTc-DPD) scintigraphy two to four times each over a five-year period. Quantitation of cardiac 99mTc-DPD retention was performed according to two established methods: measurement of heart-to-contralateral ratio (H/CL) in the anterior view (planar) and percentage of administered activity in the myocardium (SPECT). RESULTS: In total 170 datasets were analysed. Increased myocardial retention of 99mTc-DPD was demonstrable as early as 12 months from baseline. Year-on-year progression across the cohort was observed using SPECT-based quantitation, though on 30 occasions (27.8%) the change in our estimate was negative. CONCLUSIONS: The spread of our results was notably high compared to the year-on-year increases. If left unaccounted for, variance may draw fallacious conclusions about changes in disease load. We therefore urge caution in drawing conclusions solely from nuclear medicine scintigraphy on a patient-by-patient basis, particularly across a short time period.

Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy.

OBJECTIVES: Wild-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. METHODS: This 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. RESULTS: Change 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. CONCLUSION: Change in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.

Cardiac transplantation in transthyretin amyloid cardiomyopathy: Outcomes from three decades of tertiary center experience.

Aims: Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive and fatal cardiomyopathy. Treatment options in patients with advanced ATTR-CM are limited to cardiac transplantation (CT). Despite case series demonstrating comparable outcomes with CT between patients with ATTR-CM and non-amyloid cardiomyopathies, ATTR-CM is considered to be a contraindication to CT in some centers, partly due to a perceived risk of amyloid recurrence in the allograft. We report long-term outcomes of CT in ATTR-CM at two tertiary centers. Materials and methods and Results: We retrospectively evaluated ATTR-CM patients across two tertiary centers who underwent transplantation between 1990 and 2020. Pre-transplantation characteristics were determined and outcomes were compared with a cohort of non-transplanted ATTR-CM patients. Fourteen (12 male, 2 female) patients with ATTR-CM underwent CT including 11 with wild-type ATTR-CM and 3 with variant ATTR-CM (ATTRv). Median age at CT was 62 years and median follow up post-CT was 66 months. One, three, and five-year survival was 100, 92, and 90%, respectively and the longest surviving patient was Censored > 19 years post CT. No patients had recurrence of amyloid in the cardiac allograft. Four patients died, including one with ATTRv-CM from complications of leptomeningeal amyloidosis. Survival among the cohort of patients who underwent CT was significantly prolonged compared to UK patients with ATTR-CM generally (p < 0.001) including those diagnosed under age 65 years (p = 0.008) or with early stage cardiomyopathy (p < 0.001). Conclusion: CT is well-tolerated, restores functional capacity and improves prognosis in ATTR-CM. The risk of amyloid recurrence in the cardiac allograft appears to be low.

Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression.

OBJECTIVES: 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). BACKGROUND: 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. METHODS: 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. 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 showed >80% 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%). CONCLUSIONS: Reductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.

99mTc-DPD scintigraphy in immunoglobulin light chain (AL) cardiac amyloidosis.

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.

Cardiac Magnetic Resonance-Derived Extracellular Volume Mapping for the Quantification of Hepatic and Splenic Amyloid.

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<0.001; spleen: area under the curve, -0.944 [95% CI, 0.925-0.964]; spleen ECV cutoff, 0.385; sensitivity, 93.6%; specificity, 87.5%; P<0.001). There was good correlation between liver and spleen ECV and amyloid load assessed by SAP scintigraphy (r=0.504, P<0.001; r=0.693, P<0.001, respectively). There was high interobserver agreement for both the liver and spleen (ECV liver intraclass correlation coefficient, 0.991 [95% CI, 0.984-0.995]; P<0.001; ECV spleen intraclass correlation coefficient, 0.995 [95% CI, 0.991-0.997]; P<0.001) with little bias across a wide range of ECV values. 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.