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  • 1
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 9 ( 2023-1-19)
    Abstract: 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 & gt; 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 & lt; 0.001) including those diagnosed under age 65 years ( p = 0.008) or with early stage cardiomyopathy ( p & lt; 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.
    Type of Medium: Online Resource
    ISSN: 2297-055X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2781496-8
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  • 2
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. Suppl_1 ( 2021-11-16)
    Abstract: Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 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; this equates to 1.6 million carriers in the USA. We report deep phenotyping in p.V142I ATTR-CM. Hypothesis: The phenotype of p.V142I ATTR-CM is an aggressive form of ATTR CM. Methods: A retrospective study of 395 patients with p.V142I ATTR-CM from the UK National Amyloidosis Centre. Patients were diagnosed at the Centre through a comprehensive evaluation comprising clinical and functional assessment, echocardiography, radionuclide scintigraphy, histology and biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild-type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of diagnosis) were used as a comparator group. Results: At time of diagnosis, patients with p.V142I ATTR-CM had significant functional impairment by NYHA classification (NHYA ≥ III; 38.2%) and impairment of echocardiographic parameters; mean LVEF 43%, global longitudinal strain -9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid (51%) regurgitation. Uni and multivariate cox regression analysis identified troponin T, TR, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters and 5yr survival (27% v 46%, p 〈 0.001) were significantly worse than in wtATTR-CM. Conclusion: p.V142I ATTR-CM has an aggressive phenotype characterised by functional impairment, regurgitant valvular disease and systolic impairment resulting in poor survival. LV systolic impairment, TAPSE, serum troponin and TR were independent predictors of survival, whereas LV wall thickness was not, suggesting as yet unrecognised disease mechanisms.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
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  • 3
    In: European Journal of Heart Failure, Wiley, Vol. 24, No. 12 ( 2022-12), p. 2355-2363
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1388-9842 , 1879-0844
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1500332-2
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  • 4
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Introduction: Diagnostic and therapeutic advances have led to increased awareness of transthyretin cardiac amyloidosis (ATTR-CA). We sought to characterise the change in clinical phenotype of patients with ATTR-CA over the last 20-years. Methods: We studied 1967 patients diagnosed with ATTR-CA at the National Amyloidosis Centre (NAC) from 2002-2021. Results: Analysis by 5-year quartiles revealed a substantial incremental increase in patients diagnosed, with the most marked increases seen in wild-type ATTR. Increased diagnoses were accompanied by greater proportions of patients referred following bone scintigraphy and cardiac magnetic resonance imaging (3% vs 44% vs 67% vs 76%, P 〈 0.001). Over time, median duration of symptoms prior to diagnosis diminished from 36-months between 2002-2006 to 12-months between 2017-2021 (P 〈 0.001) and a greater proportion of patients had milder disease at the time of diagnosis across the 5-yearly quartiles (NAC stage 1: 34% vs 42% vs 44% vs 53%, P 〈 0.001). The latter was associated with more favourable echocardiographic parameters of structure and function, including an incremental decrease in interventricular septal thickness(18.0±3.8mm vs 17.2±2.6mm vs 16.9±2.3mm vs 16.6±2.4mm, P=0.01), which was associated with improved survival. The improved survival associated with the year of diagnosis remained significant when censoring at trial or disease modifying medication start date (2012-2016 vs. 2017-2021: HR=1.05, 95%CI[1.03-1.07], P 〈 0.001). Conclusions: Increased awareness and advances in cardiac imaging have been associated with a substantial increase in diagnosis of ATTR-CA and at a progressively earlier stage of the disease, which has contributed to improved survival in recent years. These changes may have important implications for initiation and outcome of therapy and urgently need to be factored into clinical trial design.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 5
    In: JAMA Cardiology, American Medical Association (AMA), Vol. 8, No. 9 ( 2023-09-01), p. 848-
    Abstract: 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   & amp;lt; .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   & amp;lt; .001) and ECV (mean [SD], 0.47 [0.07] vs 0.42 [0.08]; P   & amp;lt; .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   & amp;lt; .001) and ECV (mean [SD], 0.48 [0.09] vs 0.56 [0.09]; P   & amp;lt; .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.
    Type of Medium: Online Resource
    ISSN: 2380-6583
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 6
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: 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 variant ATTR-CM (ATTRv-CM) among elderly patients. Methods Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2012 and June 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. Results The study population consisted of 2164 patients with ATTR-CM (median age 79 years at diagnosis, 13.2% females, 80.4% Caucasian). ATTRv-CM was diagnosed in 20% (n=431) of the study population of whom 329 (76.3%) carried V122I, 49 (11.4%) T60A, 18 (4.2%) V30M and 35 (8.1%) 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 & lt;0.001). Univariable and multivariable binary logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.86 per year, p & lt;0.001), female sex (OR 3.0, p & lt;0.001), Afro-Caribbean ethnicity (OR 59.1, p & lt;0.001), atrial fibrillation (OR 0.65, p=0.015), ischemic heart disease (OR 0.54, p=0.007), peripheral polyneuropathy (OR 3.72, p & lt;0.001) and orthostatic hypotension (OR 3.75, p=0.001) to be independently associated with ATTRv-CM. Conclusions Up to 20% 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.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2141255-8
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  • 7
    In: European Journal of Heart Failure, Wiley, Vol. 25, No. 3 ( 2023-03), p. 335-346
    Abstract: Cardiac amyloidosis (CA) is associated with an elevation of natriuretic peptides and troponins, predicting outcome. Nevertheless, the diagnostic yield of these biomarkers has not been extensively investigated. This study aimed to evaluate the diagnostic performance for CA of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity troponin T (hs‐TnT). Methods and results Patients with suspected CA ( n  = 1149) underwent a diagnostic work‐up in three centres in Italy, France ( n  = 343, derivation cohort), and United Kingdom ( n  = 806, validation cohort). Biomarker values with either 100% sensitivity or ≥95% specificity were selected as rule‐out/rule‐in cut‐offs, respectively. In the derivation cohort, 227 patients (66%) had CA, and presented with higher NT‐proBNP and hs‐TnT. NT‐proBNP 180 ng/L and hs‐TnT 14 ng/L were selected as rule‐out cut‐offs, and hs‐TnT 86 ng/L as rule‐in cut‐off. NT‐proBNP 〈 180 ng/L or hs‐TnT 〈 14 ng/L were found in 7% of patients, and ruled out CA without false negatives. In the validation cohort, 20% of patients (2% false negatives) had NT‐proBNP 〈 180 ng/L or hs‐TnT 〈 14 ng/L, and 10% showed both biomarkers below cut‐offs (0.5% false negatives). These cut‐offs refined CA prediction when added to echocardiographic scores in patients with a haematologic disease or an increased wall thickness. In the validation cohort, the 86 ng/L hs‐TnT cut‐off ruled in 20% of patients (2% false positives). NT‐proBNP and hs‐TnT cut‐offs retained their rule‐out and rule‐in performance also in cohorts with CA prevalence of 20%, 10%, 5% and 1% derived from the original cohort through bootstrap analysis. Conclusions Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT‐proBNP 〈 180 ng/L and hs‐TnT 〈 14 ng/L reliably exclude the diagnosis, both in the overall population and subgroups referred for either AL‐CA or cardiac (pseudo)hypertrophy.
    Type of Medium: Online Resource
    ISSN: 1388-9842 , 1879-0844
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1500332-2
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  • 8
    In: European Journal of Heart Failure, Wiley, Vol. 25, No. 4 ( 2023-04), p. 515-524
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1388-9842 , 1879-0844
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1500332-2
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  • 9
    In: European Journal of Heart Failure, Wiley
    Abstract: 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 eGFR 59ml/min/1.73m 2 [IQR: 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 NT‐proBNP: 4027ng/L [2173‐6889] vs 1851ng/L [997‐3209], P 〈 0.001; median troponin‐T: 69ng/L [46‐101] vs 48ng/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 UACR. Microalbuminuria and macroalbuminuria were independently associated with mortality in the overall population (HR=1.47, 95%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. This article is protected by copyright. All rights reserved.
    Type of Medium: Online Resource
    ISSN: 1388-9842 , 1879-0844
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1500332-2
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