Regional Distribution of Extracellular Volume Quantified by Cardiac CT in Aortic Stenosis: Insights Into Disease Mechanisms and Impact on Outcomes.

BACKGROUND: Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECVCT), and has prognostic utility in several diseases. This study aims to map out regional differences in ECVCT to obtain greater insights into the pathophysiological mechanisms of ECV expansion and its clinical implications. METHODS: Three prospective cohorts were included: patients with aortic stenosis (AS) and coexisting AS and transthyretin cardiac amyloidosis were referred for a transcatheter aortic valve replacement and had ECG-gated CT angiography and Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy to differentiate between the 2 cohorts. Controls had CT angiography and cardiac magnetic resonance demonstrating no significant coronary artery disease or infarction. Global and regional ECVCT was analyzed, and its association with mortality was assessed for patients with AS. RESULTS: In 199 patients, controls (n=65; 66% male), AS (n=115), and coexisting AS and transthyretin cardiac amyloidosis (n=19) had a global ECVCT of 26.1 (25.0-27.8%) versus 29.1 (27.5-31.1%) versus 37.4 (32.5-46.6%), respectively; P<0.001. Across cohorts, ECVCT was higher at the base (versus apex), the inferoseptum (versus anterolateral wall), and the subendocardium (versus subepicardium); P<0.05 for all. Among patients with AS, epicardial ECVCT, rather than any other regional value or global ECVCT, was the strongest predictor of mortality at a median of 3.9 (max 6.3) years (adjusted hazard ratio, 1.21 [95% CI, 1.08-1.36]; P=0.002). CONCLUSIONS: Regional differences in ECVCT suggest a predilection for fibrosis and amyloid infiltration at the base, subendocardium, inferior wall, and septum more than the anterior and lateral myocardium. ECVCT can predict long-term mortality with the subepicardium demonstrating the strongest discriminatory power. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03029026 and NCT03094143.

Treatment characteristics of patients with hereditary transthyretin amyloidosis: a cohort study.

BACKGROUND: There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers. While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy. OBJECTIVES: To describe ATTRv patient and TTR-targeted therapy characteristics in a US cohort, and compare outcomes with combination therapy versus monotherapy. METHODS: We performed a retrospective cohort study with electronic health record data of patients with ATTRv seen at a single institution between January 2018 and December 2022. We collected data on symptomatology, gene mutation, disease severity, ATTRv treatment, hospitalizations, and mortality. RESULTS: One hundred sixty-two patients with ATTRv were identified. The average age at diagnosis was 65 years. 86 patients (53%) had the V122I variant. 119 patients were symptomatic, of whom 103 were started on ATTRv-specific treatment. 41 patients (40%) had cardiomyopathy only, and 53 (51%) had a mixed phenotype of cardiomyopathy and neuropathy. 38 patients (37%) received therapy with both a gene silencer and protein stabilizer. 9 patients (15%) in the monotherapy group had two or more cardiac hospitalizations after starting treatment, compared to 3 patients (9%) on combination therapy (p=0.26). The adjusted hazard ratio of all-cause mortality for the patients on combination therapy compared to monotherapy was 0.37 (0.08-1.8, p=0.21). CONCLUSIONS: While the efficacy is unproven, over one-third of patients with ATTRv are on both a stabilizer and a silencer. There were no safety issues for combination therapy. There was a trend towards improved hospitalizations and survival in patients in the combination group but this was not statistically significant. Larger studies with longer follow-up are necessary to determine benefit of combination therapy.

Neurological affection and serum neurofilament light chain in wild type transthyretin amyloidosis.

In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Diagnostic Pitfall and Clinical Characteristics of Variant Versus Wild-Type Transthyretin Amyloid Cardiomyopathy in Asian Population: The Korean Nationwide Cohort Study.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We sought to characterize the clinical characteristics of ATTR-CM in Asia. METHODS: Data from a nationwide cohort of patients with ATTR-CM from six major tertiary centres in South Korea were analysed between 2010 and 2021. All patients underwent clinical evaluation, biochemical laboratory tests, echocardiography, and transthyretin (TTR) genotyping at the time of diagnosis. The study population comprised 105 Asian ATTR-CM patients (mean age: 69 years; male: 65.7%, wild-type ATTR-CM: 41.9%). RESULTS: Among our cohort, 18% of the patients had a mean left ventricular (LV) wall thickness < 12 mm. The diagnosis of ATTR-CM increased notably during the study period (8 [7.6%] during 2010-2013 vs. 22 [21.0%] during 2014-2017 vs. 75 [71.4%] during 2018-2021). Although the duration between symptom onset and diagnosis did not differ, the proportion of patients with HF presenting mild symptoms increased during the study period (25% NYHA class I/II between 2010-2013 to 77% between 2018-2021). In contrast to other international registry data, male predominance was less prominent in wild-type ATTR-CM (68.2%). The distribution of TTR variants was also different from Western countries and from Japan. Asp38Ala was the most common mutation. CONCLUSION: A nationwide cohort of ATTR-CM exhibited less male predominance, a proportion of patients without increased LV wall thickness, and distinct characteristics of genetic mutations, compared to cohorts in other parts of the world. Our results highlight the ethnic variation in ATTR-CM and may contribute to improving the screening process for ATTR-CM in the Asian population.

Cardiac Biomarker Change at 1 Year After Tafamidis Treatment and Clinical Outcomes in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes. METHODS AND RESULTS: In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P=0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P<0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes. CONCLUSIONS: Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.

Primary Data on ATTR-Amyloidosis Prevalence Among Elderly Patients With Left Ventricular Hypertrophy in Russia.

AIM: To estimate the prevalence of amyloid cardiomyopathy (CM) caused by transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) amyloidosis among patients aged >65 years with interventricular septal (IVS) hypertrophy of ≥14 mm. MATERIAL AND METHODS: From January through August 2023, 60 patients (mean age 7.2±7.3 years, 34 (56.67%) men) were enrolled. Patients meeting the inclusion criteria underwent an echocardiographic study with determining the myocardial longitudinal strain, myocardial scintigraphy with 99mTc-pyrfotech, myocardial single-photon emission computed tomography, measurement of N-terminal fragment of brain natriuretic peptide and troponin I, and the immunochemical study of serum and urine proteins with measurement of free light chains. In the presence of grades 2 and 3 radiopharmaceutical uptake according to scintigraphy, a molecular genetic study was performed for differential diagnosis of wild-type transthyretin amyloidosis (wtATTR) and hereditary/variant (hATTR) ATTR-CM. RESULTS: According to data of myocardial scintigraphy with 99mTc-pyrfotech, grade 3 uptake in the absence of monoclonal secretion was detected in 5 (8.3%) cases and grade 2 radiotracer uptake in the absence of monoclonal secretion was detected in 6 (10%) patients. Myeloma complicated by AL amyloidosis and primary AL amyloidosis were found in 5 (8.3%) patients. CONCLUSION: Among patients aged ≥65 years with IVS hypertrophy ≥14 mm, amyloid CM was detected in 20% of cases (12 patients), including 5 cases (8.3%) of AL amyloidosis and 7 cases (11.7%) of ATTR amyloidosis.

Scintigraphic and Echocardiographic Study of Patients with Pathogenic or Probably Pathogenic Variants of the TTR Gene without Overt Cardiac Involvement. / Avaliação Cintilográfica e Ecocardiográfica em Portadores de Variantes Patogênicas ou Provavelmente Patogênicas do Gene TTR sem Envolvimento Cardíaco Manifesto.

BACKGROUND: Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the heart, the disease presents as restrictive cardiomyopathy; when it affects the peripheral and autonomic nervous system, it manifests as polyneuropathy, and is called familial amyloid polyneuropathy (FAP). There are two ATTR subtypes: wild-type ATTR, where there is no mutation, and mutant ATTR (ATTRm), which is characterized by a mutation in the gene encoding the transthyretin protein (TTR). In both subtypes, cardiac involvement is the major marker of poor prognosis. OBJECTIVES: To assess the prevalence of subclinical cardiac involvement in a sample of patients with TTR gene mutation by using pyrophosphate scintigraphy and strain echocardiography; to compare scintigraphy and strain findings; to evaluate the association between neurological manifestations (FAP) and subclinical cardiac involvement; and to analyze whether there is an association between any specific mutation and cardiac involvement. METHODS: This is a cross-sectional study with carriers of the TTR gene mutation, without cardiovascular symptoms or changes in electrocardiographic or conventional echocardiographic parameters. All patients underwent pyrophosphate scintigraphy and strain echocardiography. Subclinical cardiac involvement was defined as a Perugini score ≥ 2, heart-to-contralateral lung (H/CL) ratio ≥ 1.5 at 1 h, H/CL ≥1.3 at 3 h, or global longitudinal strain (GLS) ≤ -17%. Descriptive and analytical analyses were performed and Fisher's exact test and Mann-Whitney test were applied. A value of p < 0.05 was considered significant. RESULTS: The 23 patients evaluated had a median age of 51 years (IQR 37-57 years), 15 (65.2%) were female, 12 (52.2%) were Pardo, nine (39.1%) had systemic arterial hypertension, and nine (39.1%) had a previous diagnosis of FAP. Of the nine patients with FAP, 8 (34.8%) were on tafamidis. The associated mutations were Val142IIe, Val50Met, and IIe127Val. The median GLS in the sample was -19% (-16% to -20%). Of the 23 patients, nine (39.1%; 95% CI = 29-49%) met criteria for cardiac involvement, six (26%) by the GLS-based criteria only. There was no association between having FAP and being an asymptomatic carrier, as assessed by strain echocardiography and pyrophosphate scintigraphy (p = 0.19). The prevalence of systemic arterial hypertension, diabetes mellitus, dyslipidemia, smoking, and reduced GLS did not differ between groups. Septal e' wave velocity was the only variable that significantly differed between individuals with and without reduced GLS, with an area under the ROC curve of 0.80 (95% CI = 0.61-0.98, p = 0.027). The best diagnostic accuracy was achieved with a septal e' velocity ≤ 8.5 cm/s. There was no association between mutation type and preclinical cardiac involvement, nor between tafamidis use and lower degree of cardiac involvement (37.5% versus 40.0%, p = 0.90). CONCLUSION: Subclinical cardiac involvement was common in a sample of TTR mutation carriers without cardiac involvement. Reduced left ventricular GLS was the most frequent finding. There was no association between the presence of amyloid polyneuropathy and subclinical cardiac involvement. Type of mutation was not associated with early cardiac involvement. In this sample, the use of tafamidis 20 mg/day was not associated with a lower prevalence of subclinical cardiac involvement.

FUNDAMENTO: A amiloidose por transtirretina (ATTR) é uma doença infiltrativa causada pela deposição anormal de proteína principalmente no coração e no sistema nervoso periférico. Quando acomete o coração, a doença manifesta-se como uma cardiomiopatia restritiva e, quando afeta o sistema nervoso periférico e autônomo, apresenta-se como uma polineuropatia, podendo ser chamada de Polineuropatia Amiloidótica Familiar (PAF). Existem dois subtipos de ATTR, a ATTR selvagem, em que não há variantes genéticas, e a ATTR hereditária, caracterizada por uma variante no gene que codifica a proteína transtirretina (T\TR). Em ambos os subtipos, o envolvimento cardíaco é o principal marcador prognóstico. OBJETIVOS: Avaliar a prevalência do envolvimento cardíaco subclínico em uma amostra de pacientes com variantes genéticas no gene TTR usando a cintilografia com pirofosfato e o ecocardiograma com strain; comparar os achados cintilográficos e as medidas de strain; avaliar a associação entre PAF e o envolvimento subclínico; e analisar se existe uma associação entre uma variante genética específica e o envolvimento cardíaco. MÉTODOS: Estudo transversal com carreadores de variantes no gene TTR sem sintomas cardiovasculares e sem alterações nos parâmetros da eletrocardiografia ou do ecocardiograma convencional. Todos os pacientes foram submetidos à cintilografia com pirofosfato e à ecocardiografia com análise de strain. O envolvimento cardíaco subclínico, definido como um escore de Perugini ≥ 2, razão Coração (C)/ Hemitórax Contralateral (CL) ≥ 1,5 em uma hora, C/CL ≥ 1,3 na terceira hora, ou um strain longitudinal global (SGL) ≤ −17%. Realizadas análises descritiva e analítica, e aplicados o teste exato de Fisher e o teste de Mann-Whitney. Um valor de p<0,05 foi considerado significativo. RESULTADOS: Os 23 pacientes avaliados apresentavam uma idade mediana de 51 (37-57) anos, 15 (65,2%) eram do sexo feminino, 12 (52,2%) eram pardos, nove (39,1%) apresentavam hipertensão arterial sistêmica, e nove (39,1%) tinham um diagnóstico prévio de PAF. Dos nove pacientes com PAF, oito (34,8%) usavam tafamidis. As variantes genéticas identificadas foram Val142IIe, Val50Met e IIe127Val. O valor mediano do SGL foi −19% (-16% ­ −20%). Dos 23 pacientes, nove (39,1%; 95% CI = 29­49%) preencheram os critérios de envolvimento cardíaco, seis (26%) somente pelo critério do SGL. Não houve associação entre PAF e um carreador assintomático avaliado por ecocardiograma com análise de strain e pela cintilografia com pirofostato (p=0,19). A prevalência de hipertensão arterial sistêmica, diabetes mellitus, dislipidemia, tabagismo e SGL reduzido não foi diferente entre os grupos. A velocidade da onda e' septal foi a única variável que apresentou diferença significativa entre os indivíduos com e sem SGL reduzido, com uma área sob a curva ROC de 0,80 (IC95% = 0,61­0,98, p = 0,027). A melhor acurácia diagnóstica foi alcançada com uma velocidade e' septal ≤ 8,5 cm/s. Não houve associação entre o tipo de variante genética e o envolvimento cardíaco pré-clínico, nem entre o uso de tafamidis e este mesmo envolvimento (37,5% versus 40,0%, p = 0,90). CONCLUSÃO: O envolvimento cardíaco subclínico foi frequente em uma amostra de carreadores da variante genética do gene TTR. Um valor do SGL reduzido foi o achado mais comum. Não houve associação entre a presença de polineuropatia amiloidótica e o envolvimento subclínico. O tipo de variante genética não foi associado com envolvimento cardíaco precoce. Nesta amostra, o uso de tafamidis (20mg/dia) não foi associado com uma menor prevalência de envolvimento cardíaco subclínico.

Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry.

AIMS OF THE STUDY: Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005-2014 and prospectively from 2015 onwards. METHODS: Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually. RESULTS: Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33-4.87); it was 4.87 years (95% CI 3.14-7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48-3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4-95.3%), 68.5% (95% CI 57.4-81.7%) and 66.0% (95% CI 54.6-79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2-99.8%), 77.0% (95% CI 63.4-93.7%) and 50.6% (95% CI 31.8-80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81). CONCLUSION: During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented. Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly.

Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. OBJECTIVE: To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). METHODS: Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. RESULTS: Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. CONCLUSION: The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

ANTECEDENTES: Amiloidose hereditária por transtirretina (ATTRv) é uma doença hereditária, progressiva e fatal ainda largamente subdiagnosticada. Mutações no gene transtirretina (TTR) promovem desestabilização, desdobramento, agregação e depósito da proteína TTR em tecidos do corpo, o que faz da ATTRv uma doença de fenótipo clínico heterogêneo. OBJETIVO: Descrever a eficácia e segurança da terapia com inotersena no longo prazo em pacientes com neuropatia periférica ATTRv (ATTRv-PN). MéTODOS: Pacientes que completaram o estudo pivotal NEURO-TTR e o estudo de extensão aberta NEURO-TTR OLE migraram para este estudo e foram acompanhados por no mínimo 18 meses adicionais, em média por 67 meses, e por até 76 meses, desde o dia 1 da terapia com inotersena (D1­primeira dose de inotersena). A progressão da doença foi avaliada por medidas padronizadas. RESULTADOS: Dez pacientes com ATTRv-PN com mutação Val30Met foram incluídos. A duração média da doença no D1 era de 3 anos, e a média de idade dos pacientes era de 46,8 anos. Durante o período de acompanhamento adicional de 18 meses, a função neurológica, baseada no Neuropathy Impairment Score e no Polyneuropathy Disability Score, os aspectos de funcionalidade (Karnofsky Performance Status), nutricional e cardíacos estavam mantidos. Não se observou nenhum novo sinal de segurança. CONCLUSãO: O tratamento com inotersena foi eficaz e bem tolerado por 67 meses em média, e por até 76 meses. Nossos resultados são consistentes com os de estudos maiores de fase III.

Real life experience of tafamidis for the treatment of Spanish patients with Val30Met transthyretin amyloidosis with polyneuropathy.

INTRODUCTION: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain. METHODS: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed. RESULTS: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability. CONCLUSIONS: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.

Effect of long-term tafamidis treatment on health-related quality of life in patients with transthyretin amyloid cardiomyopathy.

AIMS: To evaluate the effect of long-term tafamidis treatment on health-related quality of life (HRQoL) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension (LTE) study. METHODS AND RESULTS: We examined change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) and clinical summary (KCCQ-CS) scores in patients who received tafamidis meglumine 80 mg for 30 months in ATTR-ACT and tafamidis (meglumine 80 mg or bioequivalent free acid 61 mg) for 30 months in the LTE study, and in patients who received placebo for 30 months in ATTR-ACT and tafamidis for 30 months in the LTE study. In ATTR-ACT, 176 and 177 patients were randomized to tafamidis 80 mg and placebo, respectively. Patients who continuously received tafamidis had a 6- to 7-point reduction in least squares (LS) mean (standard error) KCCQ-OS and KCCQ-CS scores at month 30 (-6.25 [1.53] and -7.48 [1.39]), with little or no further decline over the next 30 months (-5.92 [1.77] and -9.21 [1.88] at month 60). Patients who received placebo in ATTR-ACT had a 20-point reduction in LS mean KCCQ-OS and KCCQ-CS scores at month 30 (-19.60 [1.94] and -19.90 [2.01]), but the decline slowed after initiating tafamidis (-24.70 [3.04] and -25.30 [3.36] at month 60). CONCLUSION: Tafamidis reduced HRQoL decline in patients with ATTR-CM. Patients continuously treated with tafamidis for 60 months demonstrated stabilized HRQoL. In patients who initially received placebo in ATTR-ACT, tafamidis reduced the decline in HRQoL during the LTE study.

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.

Structures and Dynamics of ß-Rich Oligomers of ATTR (105-115) Assembly.

Transthyretin (TTR) is a tetrameric homologous protein that can dissociate into monomers. Misfolding and aggregation of TTR can lead to amyloid transthyretin amyloidosis (ATTR), which can cause many diseases (e.g., senile systemic amyloidosis, familial amyloid cardiomyopathy, and familial amyloid polyneuropathy). Despite growing evidence indicating that small oligomers play a critical role in regulating cytotoxicity, the structures of these oligomeric intermediates and their conformational transformations are still unclear, impeding our understanding of neurodegenerative mechanisms and the development of therapeutics targeting early aggregation species. The TTR monomer protein consists of various fragments prone to self-aggregation, including the residue 105-115 sequence. Therefore, our study investigated the assembly progress of ATTR (105-115) peptides using all-atom molecular dynamics simulations. The findings indicate that the probability of ß-sheet content increases with increasing numbers of peptides. Additionally, interactions between hydrophobic residues L110 and L111 are crucial for the formation of a ß-rich oligomer formation. These ß-rich oligomers may adopt ß-barrel conformations, potentially toxic oligomer species. Free-energy analysis reveals that ß-barrel conformations serve as intermediates for these ß-rich oligomers. Our insights into the structural ensemble dynamics of ATTR (105-115) contribute to understanding the physical mechanisms underlying the ß-barrel oligomers of ATTR. These findings may shed light on the pathological role of ATTR in neurodegenerative diseases and offer potential therapeutic targets.

Prevalence of moderate-severe aortic stenosis in patients with cardiac amyloidosis in a referral center.

BACKGROUND: Aortic stenosis (AS) is currently the most common valvular disease, with an estimated prevalence of over 4% in octogenarians. OBJECTIVE: To describe the prevalence of moderate-severe aortic stenosis (AS) in patients with wild type transthyretin amyloidosis (ATTRwt). Also, describe the clinical features, echocardiographic characteristics and clinical evolution. METHOD: Retrospective cohort of patients with diagnosis of ATTRwt, belonging to Hospital Italiano de Buenos Aires Institutional Amyloidosis Registry, from 30/11/2007 to 31/05/2021. Patients follow up was carried out through the institution clinical history. The prevalence of moderate-severe AE was estimated and presented as a percentage with its 95% confidence interval (95% CI). The characteristics were compared by groups according to whether or not they had moderate-severe AS. RESULTS: 104 patients with ATTRwt were included. Median follow up was 476 days [interquartile range: 192-749]. Moderate-severe AS prevalence at the ATTRwt time of diagnosis was 10.5% (n = 11; 95% CI: 5-18%). The median age of patients with AS moderate-severe at the time of diagnosis of ATTRwt was 86 years [78-91] and the male sex predominated (82%). Most of the patients had a history of heart failure (n = 8) and atrial fibrillation (n = 8) prior to the diagnosis of ATTRwt. Most of the patients were subclassified as low flow low gradient severe AS group (n = 7). Four patients underwent some intervention on the aortic valve. During follow-up, 5 patients (46%) were hospitalized for decompensated heart failure and 4 (36%) died. CONCLUSIONS: In our cohort, the coexistence of both pathologies had a similar prevalence as reported in the international literature. It was an elderly population with a high percentage of atrial fibrillation and history of heart failure. Most of the patients presented with severe AS with low flow low gradient.

ANTECEDENTES: La estenosis aórtica (EA) es actualmente la enfermedad valvular más frecuente, con una prevalencia estimada de más del 4 % en octogenarios. OBJETIVO: Describir la prevalencia de estenosis aórtica (EA) moderada-grave en pacientes con amiloidosis por transtiretina wild type (ATTRwt). Además, describir las características clínicas, ecocardiográficas y la evolución en este grupo de pacientes. MÉTODO: Estudio de cohorte retrospectiva de pacientes con diagnóstico de ATTRwt, pertenecientes al Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, en el periodo del 30/11/2007 al 31/05/2021. El seguimiento de los pacientes se realizó a través de la historia clínica electrónica de la institución. Se estimó la prevalencia de EA moderada-grave, que se presenta como porcentaje con su intervalo de confianza del 95% (IC 95%). Se compararon las características por grupos según tuvieran o no EA moderada-grave. RESULTADOS: Se incluyeron 104 pacientes con diagnóstico de ATTRwt. La mediana de seguimiento fue de 476 días [rango intercuartílico: 192-749]. La prevalencia de EA moderada-grave al momento del diagnóstico de ATTRwt fue del 10.5% (n = 11; IC95%: 5-18%). La mediana de edad de los pacientes con EA fue de 86 años [78-91] y predominó el sexo masculino (81.8%). La mayoría de los pacientes tenían el antecedente de insuficiencia cardiaca (n = 8) y fibrilación auricular (n = 8). Predominaron los pacientes con EA grave de bajo flujo y bajo gradiente (n = 7). Cuatro pacientes fueron sometidos a alguna intervención en la válvula aórtica. Durante el seguimiento, 5 pacientes (46%) tuvieron internaciones por insuficiencia cardiaca descompensada y 4 (36%) fallecieron. CONCLUSIONES: En nuestra cohorte, la coexistencia de ambas patologías tuvo una prevalencia similar a la reportada en la literatura internacional. Se trató de una población añosa con alto porcentaje de fibrilación auricular y antecedente de insuficiencia cardiaca. La mayoría presentaron EA grave de bajo flujo y bajo gradiente.