Redefining Cardiac Involvement and Targets of Treatment in Systemic Immunoglobulin AL Amyloidosis.

Importance: Cardiac amyloid infiltration is the key determinant of survival in systemic light-chain (AL) amyloidosis. Current guidelines recommend early switching therapy in patients with a nonoptimal or suboptimal response regardless of the extent of cardiac amyloid infiltration. Objective: To assess the differences between serum biomarkers, echocardiography, and cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping in characterizing cardiac amyloid, the independent prognostic role of these approaches, and the role of ECV mapping to guide treatment strategies. Design, Setting, and Participants: Consecutive patients newly diagnosed with systemic AL amyloidosis (2015-2021) underwent echocardiography, cardiac biomarkers, and CMR with ECV mapping at diagnosis. Data were analyzed from January to June 2024. Main Outcomes and Measures: The primary outcomes of the study were all-cause mortality and hematological response as defined according to validated criteria: no response (NR), partial response (PR), very good partial response (VGPR), and complete response (CR). Secondary outcomes were the depth and speed of hematological response and overall survival according to ECV. Results: Of 560 patients with AL amyloidosis, the median (IQR) age was 68 years (59-74 years); 346 patients were male (61.8%) and 214 female (38.2%). Over a median (IQR) 40.5 months 9-58 months), ECV was independently associated with mortality. In the landmark analysis at 1 month, long-term survival was independent of the achieved hematological response in ECV less than 0.30% and ECV of 0.31% to 0.40%, while it was dependent on the depth of the hematological response in ECV greater than 0.40%. In the landmark analysis at 6 months, survival was independent of the achieved hematological response in ECV less than 0.30% and dependent on achieving at least PR in ECV of 0.31% to 0.40%. Survival was dependent on achieving CR in ECV of 0.41% to 0.50% and ECV greater than 0.50%. Achieving a deep hematological response at 1 month was associated with better survival compared with 6 months in patients with ECV greater than 0.40% but not with ECV less than 0.40%. Conclusions and Relevance: This study found that ECV mapping, in systemic AL amyloidosis, is an independent predictor of prognosis, can help define the hematological response associated with better long-term outcomes for each patient and potentially inform treatment strategies.

Effect of beta-blockade on mortality in patients with cardiac amyloidosis: A systematic review and meta-analysis.

AIMS: The efficacy of beta-blockers in cardiac amyloidosis (CA) is unclear, and concerns persist that neurohormonal blockade could worsen symptoms of heart failure. We aimed to assess whether beta-blocker therapy is associated with improved survival in patients with CA. METHODS AND RESULTS: We conducted a systematic review and meta-analysis to examine the impact of beta-blocker therapy on mortality in patients with CA. A search of MEDLINE and EMBASE was performed in August 2023. Data were extracted from observational studies and synthesized with pooling and random effects meta-analysis. Thirteen studies including 4215 patients with CA were incorporated in this review (3688 transthyretin amyloid cardiomyopathy (ATTR-CM), 502 light chain amyloid cardiomyopathy (AL-CM), 25 not specified; age 74.8 ± 5.5 years, 76% male). Over half of the cohort (52%) received beta-blockers and the rate of beta-blocker withdrawal was 28%. All-cause mortality was 33% (range: 13-51%) after a median follow-up ranging from 13 to 36 months. There was an inverse association between the pooled risk of mortality and the use of beta-blocker therapy at any time point (RR 0.48, 95% CI 0.29-0.80, I2 = 83%, P = 0.005, seven studies). There was no association between mortality and beta-blocker use (RR 0.65, 95% CI 0.29-1.47, I2 = 88%, P = 0.30) in the three studies that only included patients with ATTR-CM. The three studies that included patients with both ATTR-CM and AL demonstrated an association of beta-blocker use with reduced mortality (OR 0.43, 95% CI 0.29-0.63, I2 = 4%, P < 0.001). The only study that solely included 53 patients with AL-CM, demonstrated improved survival among the 53% who were able to tolerate beta-blocker therapy (RR 0.26, 95% CI 0.08-0.79, P = 0.02). The absence of information on staging of CA is an important limitation of this study. CONCLUSIONS: Treatment with beta-blockers may be associated with a survival benefit in patients with CA, but these findings are subject to selection and survivor biases. Definitive prospective randomized trials of conventional heart failure therapies are needed in CA.

Response rates to second-line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain amyloidosis (AL) after initial Bortezomib-based regime.

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.

SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin cardiomyopathy (ATTR-CM) was an exclusion criterion in randomized clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i). OBJECTIVES: This study sought to assess the effectiveness and tolerability of SGLT2i in patients with ATTR-CM. METHODS: Data of 2,356 consecutive ATTR-CM patients (2014-2022) were analyzed: 260 (11%) received SGLT2i. After comparing the groups according to the treatment, 14 variables were significantly different-age and N-terminal pro-B-type natriuretic peptide were included in the model. A propensity score reflecting the likelihood of being treated with SGLT2i for each patient was determined using 16 variables. RESULTS: The study comprised 220 patients treated with SGLT2i (age 77 ± 2 years; 82.3% wild-type ATTR-CM; left ventricular ejection fraction 45.8% ± 11%) and 220 propensity-matched control individuals. Adequacy of matching was verified (standardized differences: <0.10 between groups). Discontinuation rate for SGLT2i was 4.5%; at 12 months, SGLT2i treatment was associated with less worsening of NYHA functional class, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and fewer new initiations of loop diuretic agent therapy. Over 28 months (Q1-Q3: 18-45 months), SGLT2i therapy was associated with lower all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003). CONCLUSIONS: SGLT2i treatment in ATTR-CM patients was well tolerated and associated with favorable effects on HF symptoms, renal function, and diuretic agent requirement over time. SGLT2i treatment was associated with reduced risk of HF hospitalization and cardiovascular and all-cause mortality, regardless of the ejection fraction, despite the effect size being likely overestimated. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM.

Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

BACKGROUND: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. METHODS: Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. RESULTS: A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)]. CONCLUSIONS: Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

Prognostic Value of a 6-Minute Walk Test in Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: The 6-minute walk test (6MWT) represents a comprehensive functional assessment that is commonly used in patients with heart failure; however, data are lacking in patients with transthyretin cardiac amyloidosis (ATTR-CA). OBJECTIVES: This study aimed to assess the prognostic importance of the 6MWT in patients with ATTR-CA. METHODS: A retrospective analysis of patients diagnosed with ATTR-CA at the National Amyloidosis Centre who underwent a baseline 6MWT between 2011 and 2023 identified 2,141 patients, of whom 1,118 had follow-up at 1 year. RESULTS: The median baseline 6MWT distance was 347 m (Q1-Q3: 250-428 m) and analysis by quartiles demonstrated an increased death rate with each distance reduction (deaths per 100 person-years: 6.3 vs 9.2 vs 13.6 vs 19.0; log-rank P < 0.001). A 6MWT distance of <350 m was associated with a 2.2-fold higher risk of mortality (HR: 2.15; 95% CI: 1.85-2.50; P < 0.001), with a similar increased risk across National Amyloidosis Centre disease stages (P for interaction = 0.761) and genotypes (P for interaction = 0.172). An absolute (reduction of >35 m) and relative worsening (reduction of >5%) of 6MWT at 1 year was associated with an increased risk of mortality (HR: 1.80; 95% CI: 1.51-2.15; P < 0.001 and HR: 1.89; 95% CI: 1.59-2.24; P < 0.001, respectively), which was similar across the aforementioned subgroups. When combined with established measures of disease progression (N-terminal pro-B-type natriuretic peptide progression and outpatient diuretic intensification), each incremental increase in progression markers was associated with an increased death rate (deaths per 100 person-years: 7.6 vs 13.9 vs 22.4 vs 32.9; log-rank P < 0.001). CONCLUSIONS: The baseline 6MWT distance can refine risk stratification beyond traditional prognosticators. A worsening 6MWT distance can stratify disease progression and, when combined with established markers, identifies patients at the highest risk of mortality.

Stratifying Disease Progression in Patients With Cardiac ATTR Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive cardiomyopathy. The clinical course varies among individuals and there are no established measures to assess disease progression. OBJECTIVES: The goal of this study was to assess the prognostic importance of an increase in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outpatient diuretic intensification (ODI) as markers of disease progression in a large cohort of patients with ATTR-CA. METHODS: We evaluated landmark survival analysis based on worsening of NT-proBNP and requirement for ODI between time of diagnosis and a 1-year visit, and subsequent mortality in 2,275 patients with ATTR-CA from 7 specialist centers. The variables were developed in the National Amyloidosis Centre (NAC) cohort (n = 1,598) and validated in the external cohort from the remaining centers (n = 677). RESULTS: Between baseline and 1-year visits, 551 (34.5%) NAC patients and 204 (30.1%) patients in the external validation cohort experienced NT-proBNP progression (NT-proBNP increase >700 ng/L and >30%), which was associated with mortality (NAC cohort: HR: 1.82; 95% CI: 1.57-2.10; P < 0.001; validation cohort: HR: 1.75; 95% CI: 1.32-2.33; P < 0.001). At 1 year, 451 (28.2%) NAC patients and 301 (44.5%) patients in the external validation cohort experienced ODI, which was associated with mortality (NAC cohort: HR: 1.88; 95% CI: 1.62-2.18; P < 0.001; validation cohort: HR: 2.05; 95% CI: 1.53-2.74; P < 0.001). When compared with patients with a stable NT-proBNP and stable diuretic dose, a higher risk of mortality was observed in those experiencing either NT-proBNP progression or ODI (NAC cohort: HR: 1.93; 95% CI: 1.65-2.27; P < 0.001; validation cohort: HR: 1.94; 95% CI: 1.36-2.77; P < 0.001), and those experiencing both NT-proBNP progression and ODI (NAC cohort: HR: 2.98; 95% CI: 2.42-3.67; P < 0.001; validation cohort: HR: 3.23; 95% CI: 2.17-4.79; P < 0.001). CONCLUSIONS: NT-proBNP progression and ODI are frequent and consistently associated with an increased risk of mortality. Combining both variables produces a simple, universally applicable model that detects disease progression in ATTR-CA.

Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis.

Importance: Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis. Objective: To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis. Design, Setting and Participants: This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months. Main Outcomes and Measures: Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis. Results: Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO2], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO2 and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO2: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]). Conclusions and Relevance: In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO2, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.

Multiorgan Dysfunction and Associated Prognosis in Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis. METHODS AND RESULTS: This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04-1.37]; P=0.01), high urea (HR, 1.23 [95% CI, 1.04-1.45]; P=0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13-1.57; P=0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01-1.42; P=0.04), hyponatremia (HR, 1.65 [95% CI, 1.28-2.11]; P<0.001), and troponin-T >56 ng/L (HR, 1.72 [95% CI, 1.46-2.03]; P<0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 [95% CI, 1.17-2.12]; P=0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 [95% CI, 1.08-1.81]; P=0.01). CONCLUSIONS: Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.

Myocardial perfusion in cardiac amyloidosis.

AIMS: Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment. METHODS AND RESULTS: Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density. CONCLUSION: Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.

Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis.

ABSTRACT: Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry-based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

Albuminuria in transthyretin cardiac amyloidosis: Prevalence, progression and prognostic importance.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy that commonly presents with concomitant chronic kidney disease. Albuminuria is common in heart failure and associated with worse outcomes, but its prevalence and relationship to outcome in ATTR-CA remains unclear. METHODS AND RESULTS: A total of 1181 patients with ATTR-CA were studied (mean age 78.1 ± 7.9 years; 1022 [86.5%] male; median estimated glomerular filtration rate 59 ml/min/1.73m2 [interquartile range: 47-74]). Albuminuria was present in 563 (47.7%) patients (499 [88.6%] with microalbuminuria and 64 [11.4%] with macroalbuminuria). Patients with albuminuria had a more severe cardiac phenotype evidenced by higher serum cardiac biomarkers (median N-terminal pro-B-type natriuretic peptide [NT-proBNP]: 4027 ng/L [2173-6889] vs. 1851 ng/L [997-3209], p < 0.001; median troponin T: 69 ng/L [46-101] vs. 48 ng/L [34-68], p < 0.001) and worse echocardiographic indices of systolic (longitudinal strain: -10.0 ± 3.6% vs. -11.6 ± 3.8%, p < 0.001) and diastolic function (E/e': 17.5 ± 6.4 vs. 16.4 ± 6.7, p < 0.001) than those with a normal urinary albumin to creatinine ratio (UACR). Microalbuminuria and macroalbuminuria were independently associated with mortality in the overall population (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.13-1.92, p = 0.005 and HR 1.87, 95% CI 1.15-3.05, p = 0.012, respectively). In a subgroup of patients (n = 349) without concomitant hypertension, diabetes mellitus or chronic kidney disease, albuminuria was also associated with mortality (HR 2.98, 95% CI 1.72-5.17, p < 0.001). At 12 months, 330 patients had a repeat UACR measurement; those in whom UACR increased by 30% or more (n = 148, 44.8%) had an increased risk of mortality (HR 1.84, 95% CI 1.06-3.19, p = 0.030). CONCLUSIONS: Albuminuria is common in patients with ATTR-CA, and more prevalent in those with a more severe cardiac phenotype. Albuminuria at diagnosis and a significant increase in UACR during follow-up are associated with mortality.

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.

British Society of Echocardiography guideline for the transthoracic echocardiographic assessment of cardiac amyloidosis.

These guidelines form an update of the BSE guideline protocol for the assessment of restrictive cardiomyopathy (Knight et al. in Echo Res Prac, 2013). Since the original recommendations were conceived in 2013, there has been an exponential rise in the diagnosis of cardiac amyloidosis fuelled by increased clinician awareness, improvements in cardiovascular imaging as well as the availability of new and effective disease modifying therapies. The initial diagnosis of cardiac amyloidosis can be challenging and is often not clear-cut on the basis of echocardiography, which for most patients presenting with heart failure symptoms remains the first-line imaging test. The role of a specialist echocardiographer will be to raise the suspicion of cardiac amyloidosis when appropriate, but the formal diagnosis of amyloid sub-type invariably requires further downstream testing. This document seeks to provide a focused review of the literature on echocardiography in cardiac amyloidosis highlighting its important role in the diagnosis, prognosis and screening of at risk individuals, before concluding with a suggested minimum data set, for use as an aide memoire when reporting.

Tracking Treatment Response in Cardiac Light-Chain Amyloidosis With Native T1 Mapping.

Importance: Cardiac magnetic resonance (CMR) imaging-derived extracellular volume (ECV) mapping, generated from precontrast and postcontrast T1, accurately determines treatment response in cardiac light-chain amyloidosis. Native T1 mapping, which can be derived without the need for contrast, has demonstrated accuracy in diagnosis and prognostication, but it is unclear whether serial native T1 measurements could also track the cardiac treatment response. Objective: To assess whether native T1 mapping can measure the cardiac treatment response and the association between changes in native T1 and prognosis. Design, Setting, and Participants: This single-center cohort study evaluated patients diagnosed with cardiac light-chain amyloidosis (January 2016 to December 2020) who underwent CMR scans at diagnosis and a repeat scan following chemotherapy. Analysis took place between January 2016 and October 2022. Main Outcomes and Measures: Comparison of biomarkers and cardiac imaging parameters between patients with a reduced, stable, or increased native T1 and association between changes in native T1 and mortality. Results: The study comprised 221 patients (mean [SD] age, 64.7 [10.6] years; 130 male [59%]). At 6 months, 183 patients (mean [SD] age, 64.8 [10.5] years; 110 male [60%]) underwent repeat CMR imaging. Reduced native T1 of 50 milliseconds or more occurred in 8 patients (4%), all of whom had a good hematological response; by contrast, an increased native T1 of 50 milliseconds or more occurred in 42 patients (23%), most of whom had a poor hematological response (27 [68%]). At 12 months, 160 patients (mean [SD] age, 63.8 [11.1] years; 94 male [59%]) had a repeat CMR scan. A reduced native T1 occurred in 24 patients (15%), all of whom had a good hematological response, and was associated with a reduction in N-terminal pro-brain natriuretic peptide (median [IQR], 2638 [913-5767] vs 423 [128-1777] ng/L; P < .001), maximal wall thickness (mean [SD], 14.8 [3.6] vs 13.6 [3.9] mm; P = .009), and E/e' (mean [SD], 14.9 [6.8] vs 12.0 [4.0]; P = .007), improved longitudinal strain (mean [SD], -14.8% [4.0%] vs -16.7% [4.0%]; P = .004), and reduction in both myocardial T2 (mean [SD], 52.3 [2.9] vs 49.4 [2.0] milliseconds; P < .001) and ECV (mean [SD], 0.47 [0.07] vs 0.42 [0.08]; P < .001). At 12 months, an increased native T1 occurred in 24 patients (15%), most of whom had a poor hematological response (17 [71%]), and was associated with an increased N-terminal pro-brain natriuretic peptide (median [IQR], 1622 [554-5487] vs 3150 [1161-8745] ng/L; P = .007), reduced left ventricular ejection fraction (mean [SD], 65.8% [11.4%] vs 61.5% [12.4%]; P = .009), and an increase in both myocardial T2 (mean [SD], 52.5 [2.7] vs 55.3 [4.2] milliseconds; P < .001) and ECV (mean [SD], 0.48 [0.09] vs 0.56 [0.09]; P < .001). Change in myocardial native T1 at 6 months was independently associated with mortality (hazard ratio, 2.41 [95% CI, 1.36-4.27]; P = .003). Conclusions and Relevance: Changes in native T1 in response to treatment, reflecting a composite of changes in T2 and ECV, are associated with in changes in traditional markers of cardiac response and associated with mortality. However, as a single-center study, these results require external validation in a larger cohort.

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.