Modeling transthyretin (TTR) amyloid diseases, from monomer to amyloid fibrils.

ATTR amyloidosis is caused by deposition of large, insoluble aggregates (amyloid fibrils) of cross-ß-sheet TTR protein molecules on the intercellular surfaces of tissues. The process of amyloid formation from monomeric TTR protein molecules to amyloid deposits has not been fully characterized and is therefore modeled in this paper. Two models are considered: 1) TTR monomers in the blood spontaneously fold into a ß-sheet conformation, aggregate into short proto-fibrils that then circulate in the blood until they find a complementary tissue where the proto-fibrils accumulate to form the large, insoluble amyloid fibrils found in affected tissues. 2) TTR monomers in the native or ß-sheet conformation circulate in the blood until they find a tissue binding site and deposit in the tissue or tissues forming amyloid deposits in situ. These models only differ on where the selection for ß-sheet complementarity occurs, in the blood where wt-wt, wt-v, and v-v interactions determine selectivity, or on the tissue surface where tissue-wt and tissure-v interactions also determine selectivity. Statistical modeling in both cases thus involves selectivity in fibril aggregation and tissue binding. Because binding of protein molecules into fibrils and binding of fibrils to tissues occurs through multiple weak non-covalent bonds, strong complementarity between ß-sheet molecules and between fibrils and tissues is required to explain the insolubility and tissue selectivity of ATTR amyloidosis. Observation of differing tissue selectivity and thence disease phenotypes from either pure wildtype TTR protein or a mix of wildtype and variant molecules in amyloid fibrils evidences the requirement for fibril-tissue complementarity. Understanding the process that forms fibrils and binds fibrils to tissues may lead to new possibilities for interrupting the process and preventing or curing ATTR amyloidosis.

The Role of Scintigraphy with Bone Radiotracers in Cardiac Amyloidosis.

Cardiac amyloidosis (CA) is caused by the myocardial deposition of misfolded proteins, either amyloid transthyretin (ATTR) or immunoglobulin light chains (AL). The paradigm of this condition has transformed, since CA is increasingly recognized as a relatively prevalent cause of heart failure. Cardiac scintigraphy with bone tracers is the unique noninvasive technique able to confirm CA without performing tissue biopsy or advanced imaging tests. A moderate-to-intense myocardial uptake (Perugini grade ≥2) associated with the absence of a monoclonal component is greater than 99% specific for ATTR-CA, while AL-CA confirmation requires tissue biopsy.

Genotype-Phenotype Correlations in ATTR Amyloidosis: A Clinical Update.

Hereditary transthyretin-related amyloidosis (hATTR) is the most common form of familial amyloidosis. It is an autosomal dominant disease caused by a pathogenic variant in the TTR gene. More than 140 TTR gene variants have been associated with hATTR, with the Val30Met variant representing the most common worldwide. The clinical phenotype varies according to the gene variant and includes predominantly cardiac, predominantly neurologic, and mixed phenotypes. The present review aims to describe the genotype-phenotype correlations in hATTR. Understanding these correlations is crucial to facilitate the early identification of the disease, predict adverse outcomes, and guide management with approved disease-modifying therapies.

Tafamidis in the Treatment of ATTR-related Cardiomyopathy: Indications and Grey Zones.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the myocardial extracellular deposition of amyloid fibrils formed from the dissociation of TTR tetramer into monomers. The rate-limiting step in TTR amyloidogenesis is the dissociation of the TTR tetramer into monomers: Tafamidis is an effective TTR-stabilizer in its native homotetrameric structure. Tafamidis is a safe and effective drug in reducing symptoms, hospitalization and mortality in accurately selected patients affected by hereditary and wild-type transthyretin amyloid cardiomyopathy.

Specific Therapy in Transthyretin Amyloid Cardiomyopathy: Future Perspectives Beyond Tafamidis.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a relatively prevalent cause of morbidity and mortality. Over the recent years, development of disease-modifying treatments has enabled stabilization of the circulating transthyretin tetramer and suppression of its hepatic production, resulting in a remarkable improvement in survival of patients with ATTR-CM. Second-generation drugs for silencing are currently under investigation in randomized clinical trials. In vivo gene editing of transthyretin has been achieving unanticipated suppression of hepatic production in ATTR-CM. Trials of antibodies inducing the active removal of transthyretin amyloid deposits in the heart are ongoing, and evidence has gathered for exceptional spontaneous regression of ATTR-CM.

Impact of Preoperative Neutrophil to Prealbumin Ratio Index (NPRI) on Short-Term Complications and Long-Term Prognosis in Patients Undergoing Laparoscopic Radical Surgery for Colorectal Cancer.

Objective: This study aims to evaluate the impact and predictive value of the preoperative NPRI on short-term complications and long-term prognosis in patients undergoing laparoscopic radical surgery for colorectal cCancer (CRC). Methods: A total of 302 eligible CRC patients were included, assessing five inflammation-and nutrition-related markers and various clinical features for their predictive impact on postoperative outcomes. Emphasis was on the novel indicator NPRI to elucidate its prognostic and predictive value for perioperative risks. Results: Multivariate logistic regression analysis identified a history of abdominal surgery, prolonged surgical duration, CEA levels ≥5 ng/mL, and NPRI ≥ 3.94 × 10-2 as independent risk factors for postoperative complications in CRC patients. The Clavien--Dindo complication grading system highlighted the close association between preoperative NPRI and both common and severe complications. Multivariate analysis also identified a history of abdominal surgery, tumor diameter ≥5 cm, poorly differentiated or undifferentiated tumors, and NPRI ≥ 2.87 × 10-2 as independent risk factors for shortened overall survival (OS). Additionally, a history of abdominal surgery, tumor maximum diameter ≥5 cm, tumor differentiation as poor/undifferentiated, NPRI ≥ 2.87 × 10-2, and TNM Stage III were determined as independent risk factors for shortened disease-free survival (DFS). Survival curve results showed significantly higher 5-year OS and DFS in the low NPRI group compared to the high NPRI group. The incorporation of NPRI into nomograms for OS and DFS, validated through calibration and decision curve analyses, attested to the excellent accuracy and practicality of these models. Conclusion: Preoperative NPRI independently predicts short-term complications and long-term prognosis in patients undergoing laparoscopic colorectal cancer surgery, enhancing predictive accuracy when incorporated into nomograms for patient survival.

Predictive nomograms based on gamma-glutamyl transpeptidase to prealbumin ratio for prognosis of hepatocellular carcinoma patients without microvascular invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) presents a significant threat to individuals and healthcare systems due to its high recurrence rate. Accurate prognostic models are essential for improving patient outcomes. Gamma-glutamyl transpeptidase (GGT) and prealbumin (PA) are biomarkers closely related to HCC. This study aimed to investigate the predictive value of the GGT to PA ratio (GPR) and to construct prognostic nomograms for HCC patients without microvascular invasion. METHODS: We retrospectively analyzed data from 355 HCC patients who underwent radical hepatectomy at Shengjing Hospital of China Medical University between December 2012 and January 2021. Patients were randomly assigned to a training cohort (n = 267) and a validation cohort (n = 88). The linearity of GPR was assessed using restricted cubic spline (RCS) analysis, and the optimal cut-off value was determined by X-tile. Kaplan-Meier survival curves and log-rank tests were used to investigate the associations between GPR and both progression-free survival (PFS) and overall survival (OS). Cox multivariate regression analysis identified independent risk factors, enabling the construction of nomograms. Time-dependent receiver operating characteristic (ROC) and calibration curves were used to evaluate the accuracy of the nomograms. Decision curve analysis (DCA) assessed the predictive value of the models. RESULTS: Patients were categorized into GPR-low and GPR-high groups based on a GPR value of 333.33. Significant differences in PFS and OS were observed between the two groups (both P < 0.001). Cox multivariate analysis identified GPR as an independent risk factor for both PFS (OR = 1.80, 95% CI: 1.24-2.60, P = 0.002) and OS (OR = 1.87, 95% CI: 1.07-3.26, P = 0.029). The nomograms demonstrated good predictive performance, with C-index values of 0.69 for PFS and 0.76 for OS. Time-dependent ROC curves and calibration curves revealed the accuracy of the models in both the training and validation cohorts, with DCA results indicating notable clinical value. CONCLUSIONS: GPR emerged as an independent risk factor for both OS and PFS in HCC patients without microvascular invasion. The nomograms based on GPR demonstrated relatively robust predictive efficiency for prognosis.

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.

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.

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.

Reappraisal of serum retinol-binding protein as a surrogate marker for retinol and discovery of a novel retinol estimation formula.

BACKGROUND & AIMS: Serum retinol (ROH) is commonly used for population level assessment of vitamin A status. High-performance liquid chromatography (HPLC) is considered most accurate method for measuring ROH. However, with the technical difficulty of using HPLC for routine assays, serum retinol-binding protein (RBP) measured by immunological assays is expected to be a surrogate marker for ROH, with reports of a close correlation between serum RBP and ROH. Nevertheless, RBP is not commonly tested to assess vitamin A status with concerns over RBP alterations under various physiopathological conditions. Thus, we reappraised the extent to which RBP could be used as a surrogate marker in representative disorders that alter serum RBP levels. As a related marker, diagnostic utility of transthyretin (TTR) was also evaluated. METHODS: To evaluate the reliability of ROH and RBP assays, specimen stability was assessed in terms of (1) storage at 25, 4, -20, and -80 °C for 1-28 days, (2) five-cycle freeze-thawing, and (3) fluorescent light exposure for 1-14 days. Sources of variation (sex, age, body mass index [BMI], and drinking habits) and reference intervals for ROH, RBP, and TTR were determined in 617 well-defined healthy individuals. To investigate the influence of disorders that affect serum RBP, patients with five diagnostic groups were enrolled: 26 with chronic kidney disease (CKD); 13 with various malignancies in advanced stages (AdM), 12 with acute bacterial infections (ABI), 6 with liver cirrhosis (LC), and 26 with simple obesity (BMI ≥ 27 kg/m2). RESULTS: The stability of RBP and ROH in serum was confirmed under all conditions. In healthy individuals, serum ROH, RBP, and TTR were appreciably high in males with a slight increase in proportion to age and BMI. The major-axis regression line between RBP (x) and ROH (y) in healthy individuals was y = x, with a correlation coefficient of 0.986. In the LC, AdM, and ABI groups, similar strong correlations were observed; however, the regression lines were shifted slightly rightward from the healthy group line, indicating a positive bias in estimating ROH. Interestingly, the same analyses between TTR and ROH revealed similar strong linear relationships in all groups; however, the regression line of each group showed a leftward (opposite) shift from the healthy group line. Based on these observations, we developed a novel regression model composed of RBP and TTR, which gave much improved accuracy in estimating ROH, even under these pathological conditions. CONCLUSIONS: The perfect RBP-ROH correlation in healthy individuals indicates the utility of RPB as a surrogate marker for ROH. Nevertheless, under RBP-altered conditions, a slight overestimation of ROH is inevitable. However, when the TTR was tested together, the bias can be corrected almost perfectly using the novel ROH estimation formula comprising RBP and TTR.

Cardiovascular Burden of the V142I Transthyretin Variant.

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

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.

The association between prealbumin concentration at admission and mortality in elderly patients with hip fractures: a cohort study.

Malnutrition is associated with complications and mortality in patients of hip fracture. Prealbumin may be more suitable than albumin to accurately predict the prognosis of hip fracture in elderly patients. We found that prealbumin concentration was nonlinearly associated with mortality in elderly patients with hip fracture, and an inflection point effect was observed. OBJECTIVE: To evaluate the association between prealbumin concentration at admission and mortality in elderly patients with hip fractures. METHODS: Elderly patients with hip fractures were screened between Jan 2015 and Sep 2019. Demographic and clinical characteristics of the patients were collected. Linear and nonlinear multivariate Cox regression models were used to identify the association between prealbumin concentration at admission and mortality. All analyses were performed using EmpowerStats and the R software. RESULTS: This cohort study included 2387 patients who met the study criteria. The mean follow-up was 37.64 months. The prealbumin concentration was 162.67 ± 43.2 mg/L. Multivariate Cox regression showed that prealbumin concentration was associated with mortality in geriatric patients with hip fracture (hazard ratio [HR] = 0.95, 95% confidence intervals [CI]: 0.93-0.97, P < 0.0001). In addition, an inflection point effect was observed in the nonlinear association. The inflection point was 162.2 mg/L. If it is less than this inflection point, then every 10 mg/L increase in prealbumin was associated with a 7% reduction in the risk of death (HR = 0.93, 95%CI: 0.90-0.96, P < 0.0001). When greater than the inflection point, there was no difference in the risk of death (HR = 0.99, 95%CI: 0.95-1.03, P = 0.5127). CONCLUSION: The prealbumin concentrations at admission were nonlinearly associated with long-term mortality in geriatric hip fractures, and 162.2 mg/L could be considered a prognostic factor of mortality risk.

Determinants of health status in older patients with transthyretin cardiac amyloidosis: a prospective cohort study.

BACKGROUND: Whether, and to what extent, frailty and other geriatric domains are linked to health status in patients with transthyretin cardiac amyloidosis (ATTR-CA) is unknown. AIMS: To determine the association of frailty with health status [defined by the Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with ATTR-CA. METHODS: Consecutive ATTR-CA patients undergoing cardiovascular assessment at a tertiary care clinic from September 2021 to September 2023 were invited to participate. KCCQ, frailty and social environment were recorded. Frailty was assessed using the modified Frailty Index (mFI), mapping 11 variables from the Canadian Study of Health and Aging (frailty ≥0.36). RESULTS: Of 168 screened ATTR-CA patients, 138 [83% men, median age of 79 (75-84) years] were enrolled in the study. Median KCCQ was 66 (50-75). wtATTR-CA was the most prevalent form (N = 113, 81.9%). The most frequent cardiac variant was Ile68Leu (17/25 individuals with vATTR-CA). Twenty (14.5%) patients were considered frail, and prevalence of overt disability was 6.5%. At multivariable linear regression analysis, factors associated with worsening KCCQ were age at evaluation, the mFI, NYHA Class, and NAC Score. Gender, ATTR-CA type, phenotype, and LVEF were not associated with health status. DISCUSSION: In older patients diagnosed with ATTR-CA, frailty, symptoms, and disease severity were associated with KCCQ. CONCLUSIONS: Functional status is a determinant of quality of life and health status in older individuals with a main diagnosis of ATTR-CA. Future research may provide more in-depth knowledge on the association of frailty in patients with ATTR-CA with respect to quality of life and prognosis.

Evaluation of Laboratory Parameters as Predictors of Mortality.

BACKGROUND: Evaluation of biomarkers as risk factors for mortality may provide early intervention and treatment for fatal diseases. We aimed to determine the usability of inexpensive and easily measurable tests in the differentiation of critically ill patients by investigating their relationship with mortality. METHODS: This study was executed by examining the sixth, third, and first month examinations of patients registered to the home health care services unit in 2022 before mortality due to any reason. This study was conducted by including 1,060 patients. All parameters were distributed non-parametrically. The difference between the dependent groups was evaluated with Friedman's two-way analysis of variance, and p < 0.05 was considered statistically significant. RESULTS: When the patients' premortem one-month, three-month, and six-month results were examined, there was an increase in mean platelet volume (MPV) values over time. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) also increased. In these two parameters, the difference between the first and third months and between the first and sixth months was statistically significant. Given the C-Reactive Protein (CRP)/Albumin Ratio (CAR) and CRP/Prealbumin results, a significant increase was observed in both ratios. A more than four-fold increase was observed in the CAR between the premortem first and sixth month results, which increased gradually over time and was statistically significant. Conclusions: NLR, PLR, MPV, CAR and CRP/Prealbumin values were statistically associated with mortality.