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Objectives: This cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography., Background: Cardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis., Methods: A total f 322 subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models., Results: Left ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e' by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality., Conclusions: Specific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Renal involvement causing progressive chronic kidney disease (CKD) is present in 70% of patients with systemic Ig light-chain (AL) amyloidosis at diagnosis. Chemotherapy that substantially suppresses free light chain production is associated with improved patient survival, but its benefit in delaying the onset of renal replacement therapy among patients who present with established advanced CKD has not been studied. To evaluate this, we studied 1000 patients enrolled in the prospective UK AL amyloidosis chemotherapy study (ALchemy). Of these, 84 patients had advanced amyloid-related CKD defined by an estimated glomerular filtration rate (eGFR) under 20 ml/min/1.73 m 2 . We determined outcomes among these 84 patients, who had a median eGFR of 10 ml/min/1.73 m 2 , in relation to response to chemotherapy evaluated at three, six, and 12 months from baseline. Patients who achieved suppression of 90% or more in their amyloidogenic free light chain (dFLC) within three months of baseline had significantly better overall survival, prolonged time to dialysis, and prolonged time to the composite endpoint of 'death or dialysis' compared to those who achieved lesser degrees of clonal response at the same time point. Even when this target of greater than 90% dFLC response was achieved but was delayed beyond 3 months, it was associated with worse outcomes. Cox regression analyses confirmed that a 90% or better dFLC response within 3 months was the only significant independent predictor of all three of these outcome measures. Thus, renal survival among patients with systemic immunologic light chain amyloidosis who present with advanced CKD is strongly dependent upon the magnitude and speed with which the underlying hematologic disorder is suppressed by chemotherapy., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Amyloidosis is caused by deposition in tissues of abnormal protein in a characteristic fibrillar form. There are many types of amyloidosis, classified according to the soluble protein precursor from which the amyloid fibrils are derived. Accurate identification of amyloid type is critical in every case since therapy for systemic amyloidosis is type specific. In ∼20-25% cases, however, immunohistochemistry (IHC) fails to prove the amyloid type and further tests are required. Laser microdissection and mass spectrometry (LDMS) is a powerful tool for identifying proteins from formalin-fixed paraffin-embedded tissues. We undertook a blinded comparison of IHC, performed at the UK National Amyloidosis Centre, and LDMS, performed at the Mayo Clinic, in 142 consecutive biopsy specimens from 38 different tissue types. There was 100% concordance between positive IHC and LDMS, and the latter increased diagnostic accuracy from 76% to 94%. LDMS in expert hands is a valuable tool for amyloid diagnosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac-isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors., Methods and Results: All patients with biopsy-proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N-terminal pro-B-type natriuretic peptide (NT pro-BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro-BNP <183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro-BNP <1420 pmol/L., Conclusions: Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro-BNP level can aid in distinguishing ATTRwt from AL amyloidosis.

Background: Cardiac involvement predicts outcome in systemic AL amyloidosis and influences therapeutic options. Current methods of cardiac assessment do not quantify myocardial amyloid burden. We used equilibrium contrast cardiovascular magnetic resonance (EQ-CMR) to quantify the cardiac interstitial compartment, measured as myocardial extracellular volume (ECV) fraction, hypothesizing it would reflect amyloid burden., Methods and Results: Sixty patients with systemic AL amyloidosis (65% men, median age 65 years) underwent conventional clinical cardiovascular magnetic resonance, including late enhancement, equilibrium contrast cardiovascular magnetic resonance, and clinical cardiac evaluation, including ECG, echocardiography, assays of N-terminal pro-brain natriuretic peptide and Troponin T, and functional assessment comprising the 6-minute walk test in ambulant individuals. Cardiac involvement in the amyloidosis patients was categorized as definite, probable, or none, suspected by conventional criteria. Findings were compared with 82 healthy controls. Mean ECV was significantly greater in patients than healthy controls (0.25 versus 0.40, P<0.001) and correlated with conventional criteria for characterizing the presence of cardiac involvement, the categories of none, probable, definite corresponding to ECV of 0.276 versus 0.342 versus 0.488, respectively (P<0.001). ECV was correlated with cardiac parameters by echocardiography (eg, Tissue Doppler Imaging [TDI] S-wave R=0.52, P<0.001) and conventional cardiovascular magnetic resonance (eg, indexed left ventricular mass R=0.56, P<0.001). There were also significant correlations with N-terminal pro-brain natriuretic peptide (R=0.69, P<0.001) and Troponin T (R=0.53, P=0.006). ECV was associated with smaller QRS voltages (R=0.57, P<0.001) and correlated with poorer performance in the 6-minute walk test (R=0.36, P=0.03)., Conclusions: Myocardial ECV measurement has potential to become the first noninvasive test to quantify cardiac amyloid burden.

Summary: Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second‐line daratumumab‐bortezomib‐dexamethasone (DVD) in AL amyloidosis in bortezomib‐exposed patients. A total of 116 patients treated with second‐line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second‐line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event‐free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2‐year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second‐line treatment in systemic AL amyloidosis in a bortezomib‐exposed population. However, the response to DVD is poorer in those with an inadequate response to first‐line bortezomib. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cytogenetic abnormalities are common in patients with amyloid light-chain (AL) amyloidosis; some are associated with poorer outcomes. This post hoc analysis of ANDROMEDA evaluated the impact of certain cytogenetic abnormalities on outcomes in this patient population. Patients with newly diagnosed AL amyloidosis were randomised 1:1 to daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) or VCd. Outcomes were evaluated in the intent-to-treat (ITT) population and in patients with t(11;14), amp1q21, del13q14, and del17p13. Overall, 321 patients had cytogenetic testing (D-VCd, n = 155; VCd, n = 166); most common abnormalities were t(11;14) and amp1q21. At a median follow-up of 20.3 months, haematologic complete response rates were higher with D-VCd vs VCd across all cytogenetic subgroups and organ response rates were numerically higher with D-VCd vs VCd across most subgroups. Point estimates for hazard ratio of major organ deterioration-PFS and -EFS favoured D-VCd over VCd for all cytogenetic subgroups. Deep haematologic responses (involved minus uninvolved free light chains [FLC] <10 mg/L or involved FLC ≤20 mg/L) were seen in more patients with D-VCd than VCd in all ITT and t(11;14) cohorts. These results support the use of D-VCd as standard of care in patients with newly diagnosed AL amyloidosis regardless of cytogenetic abnormalities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Transthyretin amyloid cardiomyopathy (ATTR‐CM) is predominantly diagnosed in men. The few available studies suggest affected women have a more favourable cardiac phenotype. We aimed to characterize sex differences among consecutive patients with non‐hereditary and two prevalent forms of hereditary (h)ATTR‐CM diagnosed over a 20‐year period. Methods and results: Analysis of deep phenotyping at presentation, changes on serial echocardiography and overall prognosis were evaluated. In total, 1732 consecutive patients were studied, comprising: 1095 with wild‐type (wt)ATTR‐CM; 206 with T60A‐hATTR‐CM; and 431 with V122I‐hATTR‐CM. Female prevalence was greater in T60A‐hATTR‐CM (29.6%) and V122I‐hATTR‐CM (27.8%) compared to wtATTR‐CM (6%). At presentation, females were 3.3 years older than males (wtATTR‐CM: 81.9 vs. 77.8 years; T60A‐hATTR‐CM: 68.7 vs. 65.1 years; V122I‐hATTR‐CM: 77.1 vs. 74.9 years). Body size significantly influenced measures of disease severity; when indexed, overall structural and functional phenotype was similar between sexes, the few significant differences suggested a mildly worse phenotype in females. No significant differences were observed in both disease progression on serial echocardiography and mortality across the overall population (p = 0.459) and when divided by genotype (wtATTR‐CM: p = 0.730; T60A‐hATTR‐CM: p = 0.161; V122I‐hATTR‐CM: p = 0.056). Conclusion: This study of a well‐characterized large cohort of ATTR‐CM patients did not demonstrate overall differences between sexes in either clinical phenotype, when indexed, or with respect to disease progression and prognosis. Non‐indexed wall thickness measurements may have contributed to both under‐representation and delays in diagnosis for affected females and highlights the potential role of utilizing indexed echocardiographic parameters for a more accurate assessment of patients at diagnosis and for disease prognostication. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis.Methods: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET.Results: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks.Conclusions: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018). [ABSTRACT FROM AUTHOR]

Summary: 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 < 0·0001), uPCR (r = 0·422, P < 0·0001) as well as both fractional excretion of phosphate and urate (r = 0·563, P < 0·0001). Log uRBPCR at diagnosis was a strong independent predictor of end‐stage renal disease {hazard ratio [HR] 2·65, [95% confidence interval (CI) 1·06–6·64]; P = 0·038}, particularly in patients with an eGFR >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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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 < 0.001; Stage III vs. II, HRs 1.64–2.25; P < 0.001–0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow‐up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58–3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86–4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I‐hATTR‐CM than in wtATTR‐CM (43% vs. 27% at 12 months of follow‐up; P = 0.003). Conclusions: National Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR‐CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow‐up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I‐hATTR‐CM than in wtATTR‐CM. [ABSTRACT FROM AUTHOR]

Amyloidosis is a general term for diseases characterised by the deposition of insoluble amyloid fibrils in organs or tissues, leading to organ dysfunction and, in many cases, death. Amyloid fibrils are derived from soluble precursor proteins, with the number of known amyloidogenic proteins increasing over time. The identity of the precursor protein often predicts the disease phenotype, although many of the amyloidoses have overlapping clinical features. Most patients with amyloidosis will require biopsy of an involved organ or tissue to confirm the diagnosis. Cardiac transthyretin amyloidosis, however, may be diagnosed without a biopsy provided stringent criteria are met. Where amyloid is confirmed histologically, the identity of the amyloidogenic protein must be determined, given several of the amyloidoses have disease-specific therapies. Laser capture microdissection and tandem mass spectrometry, LCM-MS, has revolutionised amyloid subtyping, being able to identify the amyloidogenic protein more reliably than antibody-based methods such as immunohistochemistry. Here we summarise the biopsy approach to amyloidosis, as well as the non-biopsy diagnosis of cardiac transthyretin amyloidosis. Proteomic and antibody-based methods for amyloid subtyping are reviewed. Finally, an algorithm for confirming the diagnosis of amyloidosis is presented. [ABSTRACT FROM AUTHOR]

Summary: Bortezomib is standard treatment in AL amyloidosis (AL), but is contraindicated in patients with significant neuropathy. Carfilzomib, a second‐generation proteosomal inhibitor, results in a lower incidence of neuropathy than bortezomib, but data in AL is scant. We report a cohort of five AL patients treated with upfront carfilzomib. All had cardiac, peripheral and autonomic neuropathy at presentation. All achieved at least a very good partial haematological response. There was no worsening in cardiac function, peripheral or autonomic neuropathy. Carfilzomib is an effective upfront treatment option in AL patients with peripheral and/or autonomic neuropathy (without severe cardiac or renal involvement). [ABSTRACT FROM AUTHOR]

The tissue diagnosis of amyloidosis and confirmation of fibril protein type, which are crucial for clinical management, have traditionally relied on Congo red (CR) staining followed by immunohistochemistry (IHC) using fibril protein specific antibodies. However, amyloid IHC is qualitative, non‐standardised, requires operator expertise, and not infrequently fails to produce definitive results. More recently, laser dissection mass spectrometry (LDMS) has been developed as an alternative method to characterise amyloid in tissue sections. We sought to compare these techniques in a real world setting. During 2017, we performed LDMS on 640 formalin‐fixed biopsies containing amyloid (CR+ve) comprising all 320 cases that could not be typed by IHC (IHC−ve) and 320 randomly selected CR+ve samples that had been typed (IHC+ve). In addition, we studied 60 biopsies from patients in whom there was a strong suspicion of amyloidosis, but in whom histology was non‐diagnostic (CR–ve). Comprehensive clinical assessments were conducted in 532 (76%) of cases. Among the 640 CR+ve samples, 602 (94%) contained ≥2 of 3 amyloid signature proteins (ASPs) on LDMS (ASP+ve) supporting the presence of amyloid. A total of 49 of the 60 CR‐ve samples were ASP–ve; 7 of 11 that were ASP+ve were glomerular. The amyloid fibril protein was identified by LDMS in 255 of 320 (80%) of the IHC–ve samples and in a total of 545 of 640 (85%) cases overall. The LDMS and IHC techniques yielded discordant results in only 7 of 320 (2%) cases. CR histology and LDMS are corroborative for diagnosis of amyloid, but LDMS is superior to IHC for confirming amyloid type. [ABSTRACT FROM AUTHOR]

The article focuses on a study about the detection of extracellular volume overload and sarcopenia in systemic AL amyloidosis with the application of bioimpedance vector analysis. An overview of Systemic AL amyloidosis, which causes heart failure (HF) and proteinuric chronic kidney disease (CKD) such that both extracellular volume (ECV) overload and sarcopenia, is presented.

Purpose: Transthyretin (ATTR) amyloidosis is a rare but serious infiltrative disease associated with a wide spectrum of morphologic and functional cardiac involvement. 99mTc-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), initially developed as a bone-seeking radiotracer, is remarkably sensitive for imaging cardiac ATTR amyloid deposits. Our aim was to investigate the feasibility and utility of estimating 99mTc-DPD uptake in myocardial tissue; this has the potential to yield reliable quantitative information on cardiac amyloid burden, which is urgently required to monitor disease progression and response to novel treatments. Methods: Three methods of quantitation were developed and tested on 74 patients with proven cardiac ATTR amyloidosis who had recently undergone 99mTc-DPD planar whole-body imaging and SPECT-CT. Quantitative results were compared to measurements of extracellular volume fraction (ECV) by cardiac magnetic resonance imaging, a validated technique for measuring amyloid burden. Results: An experienced clinician graded uptake using a widely-used visual scoring system as 1 (n = 15), 2 (n = 39) or 3 (n = 20). Linear correlations between the SPECT and ECV data (p < .001) were demonstrated. None of the methods showed that 99mTc-DPD uptake in the heart was significantly greater in patients with grade-3 uptake than in those with grade-2 uptake. Conclusions: Quantitation of 99mTc-DPD uptake in cardiac transthyretin amyloid deposits is complex and is hindered by competition for radiotracer with amyloid in skeletal muscle. The latter underlies differences in uptake between grade-2 and grade-3 patients, not cardiac uptake. [ABSTRACT FROM AUTHOR]

Purpose: 18F-Florbetapir has been reported to show cardiac uptake in patients with systemic light-chain amyloidosis (AL). This study systematically assessed uptake of 18F-florbetapir in patients with proven systemic amyloidosis at sites outside the heart.Methods: Seventeen patients with proven cardiac amyloidosis underwent 18F-florbetapir PET/CT imaging, 15 with AL and 2 with transthyretin amyloidosis (ATTR). Three patients had repeat scans. All patients had protocolized assessment at the UK National Amyloidosis Centre including imaging with 123I-serum amyloid P component (SAP). 18F-Florbetapir images were assessed for areas of increased tracer accumulation and time-uptake curves in terms of standardized uptake values (SUVmean) were produced.Results: All 17 patients showed 18F-florbetapir uptake at one or more extracardiac sites. Uptake was seen in the spleen in 6 patients (35%; 6 of 9, 67%, with splenic involvement on 123I-SAP scintigraphy), in the fat in 11 (65%), in the tongue in 8 (47%), in the parotids in 8 (47%), in the masticatory muscles in 7 (41%), in the lungs in 3 (18%), and in the kidney in 2 (12%) on the late half-body images. The 18F-florbetapir spleen retention index (SRI) was calculated. SRI >0.045 had 100% sensitivity/sensitivity (in relation to 123I-SAP splenic uptake, the current standard) in detecting splenic amyloid on dynamic imaging and a sensitivity of 66.7% and a specificity of 100% on the late half-body images. Intense lung uptake was seen in three patients, one of whom had lung interstitial infiltration suggestive of amyloid deposition on previous high-resolution CT. Repeat imaging showed a stable appearance in all three patients suggesting no early impact of treatment response.Conclusion: 18F-Florbetapir PET/CT is a promising tool for the detection of extracardiac sites of amyloid deposition. The combination of uptake in the heart and uptake in the spleen on 18F-florbetapir PET/CT, a hallmark of AL, suggests that this tracer holds promise as a screening tool for AL. [ABSTRACT FROM AUTHOR]

Repeat cycles of miridesap, to deplete circulating serum amyloid P component (SAP), followed by the anti-SAP antibody, dezamizumab, cleared visceral amyloid deposits in patients with systemic amyloidosis. Making amyloid vanish: Fatal systemic amyloidosis is caused by extracellular amyloid deposition that disrupts tissue structure and function. The normal plasma protein, serum amyloid P component (SAP), is always present within amyloid deposits. Richards et al. now show that previous depletion of circulating SAP by the drug, miridesap, uniquely enables subsequent administration of the humanized anti-SAP antibody, dezamizumab, to patients with systemic amyloidosis. Dezamizumab bound to residual SAP in the amyloid deposits and triggered their removal. Repeat cycles of miridesap followed by dezamizumab progressively removed amyloid from the liver, spleen, and kidneys of the patients. Evidence of clinical benefit suggests that this new approach has potential to improve management and outcome for patients with systemic amyloidosis. Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier: NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of 123I-labeled SAP or of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests. 123I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis. [ABSTRACT FROM AUTHOR]

Cardiac involvement and presenting dFLC (difference between involved and uninvolved free light chains) are independent predictors of outcome in systemic AL amyloidosis. These markers have limited prognostic utility in patients surviving the initial months following diagnosis. Here we assessed immunoparesis, as determined by novel heavy+light chain (HLC) immunoassays, as a prognostic marker for survival in AL amyloidosis. HLC measurements identified immunoparesis of at least one immunoglobulin (Ig) isotype in 145 (85%) patients; and severe immunoparesis (≥2 Ig isotypes suppressed by >50% below normal levels) in 29 (17%) patients. Median overall survival (OS) on intention to treat (ITT) analysis was 26·2 months. In the ITT cohort, dFLC >180 mg/l was associated with shorter OS ( P = 0·05); whereas HLC immunoparesis was not prognostic. On a landmark analysis of 127 patients alive at 6 months, presenting dFLC was not prognostic for OS ( P = 0·33) and severe HLC immunoparesis trended towards poorer survival (20·2 vs. 42·8 months; P = 0·09). In the subset of patients with cardiac involvement, severe HLC immunoparesis conferred very poor outcome (median OS 8·8 vs. 29·9 months, P = 0·007). In conclusion, severe HLC immunoparesis is an independent marker of long-term poor prognosis in AL patients with cardiac involvement. The pathophysiological significance of this observation needs further study. [ABSTRACT FROM AUTHOR]

Aims To assess the prognostic value of myocardial pre-contrast T1 and extracellular volume (ECV) in systemic amyloid lightchain (AL) amyloidosis using cardiovascular magnetic resonance (CMR) T1 mapping. Methods and results One hundred patients underwent CMR and T1 mapping pre- and post-contrast. Myocardial ECV was calculated at contrast equilibrium (ECVi) and 15 min post-bolus (ECVb). Fifty-four healthy volunteers served as controls. Patients were followed up for a median duration of 23 months and survival analyses were performed. Mean ECVi was raised in amyloid (0.44±0.12) as was ECVb (mean 0.44±0.12) compared with healthy volunteers (0.25±0.02), P , 0.001. Native pre-contrast T1 was raised in amyloid (mean 1080±87 ms vs. 954 ±34 ms, P , 0.001). All three correlated with pre-test probability of cardiac involvement, cardiac biomarkers, and systolic and diastolic dysfunction. During follow-up, 25 deaths occurred. An ECVi of .0.45 carried a hazard ratio (HR) for death of 3.84 [95% confidence interval (CI): 1.53–9.61], P= 0.004 and pre-contrast T1 of .1044 ms= HR 5.39 (95% CI: 1.24–23.4), P= 0.02. Extracellular volume after primed infusion and ECVb performed similarly. Isolated post-contrast T1 was non-predictive. InCox regression models, ECVi was independently predictive of mortality (HR= 4.41, 95% CI: 1.35–14.4) after adjusting for E:E′, ejection fraction, diastolic dysfunction grade, and NT-proBNP. Conclusion Myocardial ECV (bolus or infusion technique) and pre-contrast T1 are biomarkers for cardiac AL amyloid and they predict mortality in systemic amyloidosis. [ABSTRACT FROM AUTHOR]

The article looks at a guideline for the management of amyloid light-chain (AL) amyloidosis. Topics discussed include use of first line treatment with combination chemotherapy, use of Thalidomide in combination with cyclophosphamide and dexamethasone, and need of taking precautions during the use of Thalidomide in patients with cardiac stage III disease.

The article looks at a guideline for the diagnosis and investigation of amyloid light-chain (AL) amyloidosis provided by the British National Amyloidosis Centre. Topics discussed include histological diagnosis of AL amyloidosis, use of Bone marrow aspirate and trephine biopsy in diagnosis, and role of echocardiography in assessing amyloid involvement.

Objectives: This study was devised to describe the different cardiac magnetic resonance (CMR) appearances in light chain amyloid (AL) and transthyretin-related amyloidosis (ATTR). Background: CMR is increasingly used to investigate patients with suspected amyloidosis. Global subendocardial late gadolinium enhancement (LGE) has been reported as typical of AL amyloidosis, whereas different patterns have been noted in ATTR amyloidosis. Methods: We performed de novo analyses on original DICOM magnetic resonance imaging in 46 patients with cardiac AL amyloidosis and 51 patients with ATTR type who had been referred to a specialist amyloidosis center between 2007 and 2012 after CMR. Histological examination was performed in all cases, with immunohistochemistry, to confirm systemic amyloidosis. Results: Patients' median age was 68 ± 10 years, and 74% were male. Left ventricular mass was markedly increased in ATTR amyloidosis (228 g [202 to 267 g]) compared with AL type (167 g [137 to 191 g]) (p < 0.001). LGE was detected in all but 1 cardiac amyloidosis patient (AL type) and was substantially more extensive in ATTR compared with AL amyloidosis. Ninety percent of ATTR patients demonstrated transmural LGE compared with 37% of AL patients (p < 0.001). Right ventricular LGE was apparent in all ATTR patients but in only 33 AL patients (72%) (p < 0.001). Despite these findings, survival was significantly better in cardiac ATTR amyloidosis compared with AL type. We derived an LGE scoring system (Query Amyloid Late Enhancement) that independently differentiated ATTR from AL amyloidosis and, when incorporated into a logistic regression model with age and wall thickness, detected ATTR type with 87% sensitivity and 96% specificity. Conclusions: Transmural patterns of LGE distinguished ATTR from AL cardiac amyloidosis with high accuracy in this real-world analysis of CMR. Precise diagnosis of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development. [Copyright &y& Elsevier]

Aims Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant. Methods and results Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45–78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years. Conclusion Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging. [ABSTRACT FROM PUBLISHER]

High-dose chemotherapy with autologous stem cell transplantation (SCT) is widely used as a treatment for systemic AL amyloidosis, but its efficacy has not been proved and it has substantial toxicity in this setting. We report here the outcome of 92 patients evaluated at the UK National Amyloidosis Centre who underwent SCT for AL amyloidosis between 1994 and 2004 in various British centres. Median age was 53 years and median of two organs were affected by amyloidosis. All-cause day 100 mortality [treatment-related mortality (TRM)] was 23% for the entire cohort, although this was substantially greater for patients treated from 1994 to 1998 (15/47, 32%) than subsequently (6/45, 13%). Independent factors significantly associated with TRM on multivariate analysis were: number of affected organs, performance status, serum albumin and age. Response of the underlying clonal disease, defined by ≥50% reduction in the aberrant serum-free light chain concentration, occurred in 83% of evaluable patients. Overall median survival was 5·3 years, and was 8·5 years among patients who survived beyond day 100. Despite recent refinements in patient selection, TRM remains substantial during SCT for systemic AL amyloidosis, and its place in the therapeutic armamentarium for this disease needs to be defined in randomised controlled clinical studies. [ABSTRACT FROM AUTHOR]

The article offers information on systemic light-chain (AL) amyloidosis involving the kidneys, heart, and liver. Topics discussed include patients with suspected cardiac amyloidosis, difficulties in determining extent of amyloid deposition outside of vital organs, and role of Tc-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid as a sensitive tracer for cardiac transthyretin amyloid deposits.

The article presents a case study of a 47-year-old female patient with a history of breast carcinoma who was treated for systemic AA amyloidosis associated with Hodgkin lymphoma, and it mentions serum amyloid A (SAA) and positron emission tomography-computed tomography tests. Drug therapy using doxorubicin, bleomycin, vinblastine and dacarbazine is examined, along with AA amyloid fibrils and successful medical treatments.

In this issue of Blood, Ciheira et al report long-term outcomes of 421 Patients with AL amyloidosis undergoing autologous stem cell transplantation (ASCT) at a single center. Patients who achieved a complete hematologic response (CR) had impressively long hematologic remission, event-free survival (EFS) and overaIl survival (OS) of 12.7 years, 8.3 years, and 13.2 years. respectively. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac involvement in immunoglobulin light chain amyloidosis (AL) is the major determinant of survival. Cardiac response to chemotherapy is conventionally assessed by serum brain natriuretic peptide (NT-proBNP) and echocardiography, but neither quantify amyloid burden. Hypothesis: We assessed the hypothesis that CMR with T1 mapping and extracellular volume (ECV) can evaluate amyloid burden in cardiac AL amyloidosis tracking changes over time at 3 months, 6 months and 1 year after the initiation of chemotherapy. Methods: 94 patients with cardiac AL amyloidosis were studied serially using CMR with T1 mapping and ECV at baseline, 3 months, 6 months and 1 year post-chemotherapy. Results: At 6 months, 62% of patients achieved a complete response (CR) or very good partial haematological response (VGPR) to chemotherapy, and 38% a partial response (PR) or no response (NR). Amyloid regression was detectable in only 1 patient, however, there was amyloid progression in 34% of patients (Figure, panel A). Although this occurred in the PR group, it also occurred in the CR and VGPR groups (63%). At one year, 64% of patients achieved a good haematological response. Regression of amyloid was seen in 30% of patients (Figure, panel B), all with CR or VGPR and 0 patients in PR or NR (p<0.05). However, not every patient with CR or VGPR had amyloid regression by CMR, having 4 of these patients amyloid progression. Interestingly, these 4 patients achieved the good haematological response late (after the first 6 months of chemotherapy). 46% of patients with changes in ECV consistent with amyloid regression had also visual changes in the pattern of late gadolinium enhancement. Amyloid regression was associated with significant reduction in LV mass and NT-pro BNP (p<0.05) and in native T1 (p<0.01). Conclusion: In newly diagnosed and treated AL amyloidosis, CMR demonstrates the dynamic biology of infiltration: increasing rapidly, particularly if chemotherapy fails to switch off light chain production promptly; regressing more slowly (by one year) if effective. Serial monitoring of myocardial infiltration has the potential for new AL amyloidosis therapeutic regimes based on myocardial organ response. [ABSTRACT FROM AUTHOR]