Transthyretin Concentrations Research Articles

Low transthyretin concentration linked to adverse prognosis in elderly inpatients

BackgroundTo investigate the association between low transthyretin (prealbumin) concentration and mortality or readmission for all causes in elderly inpatients.MethodsThis analysis is based on a prospective cohort study conducted from September 2018 to April 2019 in ten wards of three tertiary referral hospitals in Beijing. Patients aged 65 years or older were enrolled, and their clinical data, laboratory test results, and auxiliary test results for patients were collected. A three-year follow-up was conducted with patients. Based on the 5th and 95th percentiles of transthyretin concentration, patients were split into three groups. The correlation between transthyretin concentration and the outcome of elderly hospitalized patients was investigated. The primary outcome of the research was death or readmission from all causes within three years.ResultsAmong the 636 individuals in the study, 335 (52.7%) were males, with a median age of 74.7 years (interquartile range [IQR]: 69.3–80.1). During a median follow-up period of 1,099.0 days (IQR: 1,016.3-1,135.0), 363 individuals (57.0%) experienced all-cause mortality or readmission events. Patients with transthyretin concentrations at or below the 5th percentile had a significantly increased risk of all-cause mortality or readmission compared to those with concentrations between the 5th and 95th percentiles (hazard ratio [HR]: 2.25; 95% confidence interval [CI]: 1.55–3.26). Even after adjusting for potential confounders, low transthyretin concentration remained an independent risk factor for poor prognosis in elderly inpatients (HR: 1.84; 95% CI: 1.03–3.28). Since women have consistently lower baseline transthyretin levels than men, we performed gender-specific analysis. We found that low transthyretin concentration is an independent risk factor for adverse prognosis in elderly male inpatients (HR: 2.99; 95% CI: 1.35–6.62) but not in females.ConclusionsLow transthyretin concentrations are associated with increased all-cause mortality or readmission in elderly inpatients, particularly among male patients.Graphical

Concentration of HSPA1A and transthyretin proteins in the blood serum of patients with bipolar disorder

IntroductionInsufficient knowledge about the pathophysiological processes in bipolar disorder (BD) leads to difficulties in differentiating this disorder from other affective disorders. Quantitative analysis of serum protein profiles in BD expands our understanding of the pathophysiology of the disease and may aid in subsequent diagnosis. As a result of a previously conducted comparative mass spectrometric study of serum proteins in patients with depression, bipolar disorder and healthy donors, increased expression of Heat Shock 70kDa Protein1A (HSPA1A) and transthyretin was identified.ObjectivesDetermination of HSPA1A and transthyretin concentrations in the blood serum of patients with mental disorders.MethodsBlood serum of 28 patients with bipolar disorder aged 49 years [33;52], 30 patients with recurrent depressive disorder aged 40 years [31; 51] and 130 patients with schizophrenia aged 38 years [31;49], as well as 20 mentally and somatically healthy individuals aged 35 years [31;40] was studied. The amount of Heat shock protein 1A (HSPA1A) and Transthyretin (thyroxine and retinol transport protein) was determined using a Enzyme-linked Immunosorbent Assay Kit from Homo sapiens (Cloud-Clone Corp). Statistical data processing was carried out in the Statistica 12.0 program.ResultsA statistically significant (p = 0.016) increase in the level of HSPA1A was found in patients with BD (0.84 [0.59; 1.09] ng/ml), compared with healthy individuals (0.61 [0.51; 0.77] ng/ml). HSPA1A plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins. It is known that this protein is involved in the embryonic development of the central nervous system, as well as in neuroprotection by preventing the death of neurons due to its anti-apoptotic properties. A statistically significant (p = 0.047) increase in the level of transthyretin was found in patients with BD 21.8 рg/ml, compared with healthy individuals 19.4 pg/ml. Transthyretin plays an important role in ensuring the normal state of the central nervous system and is involved in cognitive processes.ConclusionsThus, the HSPA1A and transthyretin are probably involved in the pathogenesis of BD and can be proposed as be proposed as an additional paraclinical criterion for differential diagnosis.Support by RSF №23-75-00023.Disclosure of InterestNone Declared

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

Evaluation of Albumin, Transferrin and Transthyretin in Inflammatory Bowel Disease Patients as Disease Activity and Nutritional Status Biomarkers.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is often accompanied by malnutrition that manifests itself as nutrient deficiencies and body mass loss or deficit. The purpose of this study is to evaluate the utility of albumin, transferrin and transthyretin levels in the assessment of nutritional status and IBD activity. The case-control study included 82 IBD patients. The serum concentrations of albumin, transferrin and transthyretine were determined by a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). Significantly lower median concentrations of albumin were found in the IBD patients vs. controls and in CD patients compared to the UC patients. Significantly higher median transthyretin concentrations were found in the IBD patients compared to the healthy subjects. There were no significant differences in median transferrin concentrations between the IBD patients and the healthy subjects. Significantly higher albumin levels were found in IBD patients in remission compared to patients with moderate and severe exacerbation of IBD symptoms. There were no significant differences in the median transferrin or transthyretin levels in patients with IBD depending on disease activity. No differences were identified in the median transferrin or transthyretin levels in the IBD patients according to nutritional status. The median albumin concentrations in the IBD subjects were significantly higher in patients with normal body fat, normal BMI and normal waist circumferences compared to those with an abnormal nutritional status. The albumin levels reflect both nutritional status and disease activity and therefore cannot be considered a prognostic marker of malnutrition in IBD. As regards the utility of transferrin and transthyretin as markers of activity and nutritional status in IBD patients, further studies are required.

Chelation Therapy Associated with Antioxidant Supplementation Can Decrease Oxidative Stress and Inflammation in Multiple Sclerosis: Preliminary Results.

An imbalance of oxy-inflammation status has been involved in axonal damage and demyelination in multiple sclerosis (MS). The aim of this study was to investigate the efficacy of an antioxidant treatment (calcium disodium ethylenediaminetetracetic acid-EDTA) chelation therapy associated with a micronutrient complex in MS patients. A total of 20 MS patients and 20 healthy subjects, enrolled as a control group (CTR), were recruited. We measured the plasma ROS production and total antioxidant capacity (TAC) by a direct assessment using Electron Paramagnetic Resonance; activities of the antioxidant system (thiols' redox status and enzymes); and the urinary presence of biomarkers of oxidative stress by immunoenzymatic assays. We also evaluated the levels of inflammation by plasmatic cytokines (TNFα, IL-1β, and IL-6) and assessed the sICAM levels, as well as the nitric oxide (NO) catabolism and transthyretin (TTR) concentration. Comparing CTR and MS, in the latter ROS production, oxidative damage, inflammatory biomarkers, and NO metabolite concentrations results were significantly higher, while TAC was significantly lower. Treatment in MS induced significant (p < 0.05) down-regulating of pro-inflammatory sICAM1, TNF-α, IL6, as well as biomarkers of lipid peroxidation and DNA damage production. The protective effect exhibited may occur by decreasing ROS production and increasing antioxidant capacity, turning into a more reduced thiols' status.

Rat Serum Osteocalcin Concentration Is Decreased by Restriction of Energy Intake

We studied the effects of energy restriction on serum osteocalcin concentration and bone formation rate in rats. The experiment was designed to achieve energy restriction by reducing the carbohydrate intake while providing identical quantities of protein, fat, vitamins and minerals. Energy intakes of three groups of post-weaning male rats were restricted by 20, 40 and 60% for 4 wk. Serum calclum, phosphorus, transthyretin, triiodothyronine (T3), thyroxine (T4), 1,25-dihydroxycholecalciferol, 25-hydroxycholecalciferol and immunoreactive parathyroid hormone (iPTH) concentrations were determined. Energy restriction (20, 40 and 60%) produced a significant and gradual drop of serum osteocalcin concentrations, although the serum concentrations of its key regulators, i.e., 1,25-dihydroxycholecalciferol and iPTH, were not significantly affected. On the contrary, serum concentrations of calcium, phosphorus, transthyretin, T3 and T4 were significantly lower in the energy-restricted groups. However, our results do not support their implication in the regulation of serum osteocalcin synthesis by energy intake. Serum osteocalcin concentration was positively correlated with bone mineral apposition (r = 0.50, P < 0.05) and bone mineralization (r = 0.50, P < 0.05) rates suggesting that its decrease resulted from a reduction of bone formation, and not from abnormal mineralization, because osteoid seam thickness was not modified. Energy intake seems to be an important determinant of serum osteocalcin concentration and bone formation; however, the exact mechanism underlying this regulation remains to be determined.

Abstract 14649: Low Plasma Transthyretin is Associated With All-Cause and Cardiovascular Mortality in the General Population

Introduction: Transthyretin tetramer destabilization is the rate-limiting step in transthyretin cardiac amyloidosis, which is an underrecognized contributor to heart failure and mortality in older adults. Evidence suggests that low plasma transthyretin is an in vivo marker of transthyretin tetramer instability. Hypothesis: We tested the hypothesis that low plasma transthyretin genetically and observationally associates with all-cause and cardiovascular mortality. Methods: We genotyped 102,204 individuals and measured plasma transthyretin concentrations in 19,619 individuals from two studies of the Danish general population, the Copenhagen City Heart Study and the Copenhagen General Population Study. We first tested whether genetic variants in TTR , which associated with increasing transthyretin tetramer instability, also associated with lower plasma transthyretin and higher risk of all-cause and cardiovascular mortality. Second, we tested whether low plasma transthyretin associated with higher risk of all-cause and cardiovascular mortality. Results: Compared to p.T139M, a well-known transthyretin stabilizing mutation, TTR genotype was associated with stepwise lower transthyretin concentrations of -20% for wild-type and -30% for heterozygotes for “Other mutations” (p.V142I, p.H110N, p.D119N). The corresponding hazard ratios (HR) for all-cause and cardiovascular mortality were 1.37(95% CI: 1.06-1.77) and 1.63(0.92-2.89) in wild-types, and 1.66(0.95-2.88) and 2.23(0.78-6.34) in carriers of “Other mutations”, respectively (Figure). In adjusted observational analysis individuals with plasma transthyretin ≤5 th percentile (&lt;19.1 mg/dL) versus 6-95 th percentile (reference) had HRs of 1.39(1.17-1.64) and 1.66(1.17-2.38) for all-cause and cardiovascular mortality. Conclusions: Genetically and observationally low transthyretin concentrations are associated with higher risk of all-cause and cardiovascular mortality.

Effect of Traditional Complementary Porridges Enriched with Cashew Kernel (Anacardium occidental) and Vegetable Cortea (Corchorus olitorius L.) on the Nutritional Protein Profile and Inflammatory Status of Moderately Acutely Malnourished Children in Côte d’Ivoire

This study aims to study the effect of the enrichment of traditional porridge on the nutritional and inflammatory protein profile of Moderately Acutely Malnourished (MAM) aged 6 to 59 months with a view to their nutritional rehabilitation. To achieve this, four groups of 75 Moderately Acutely Malnourished (MAM) children were fed four types of porridge: non-enriched porridge (BC1), porridge enriched with Anacardium occidentalis (BC2), porridge enriched with Corchorus olitorius leaves (BC3) and porridge enriched with both Corchorus olitorius leaves and Anacardium occidental (BC4). Nutritional (Albumin, Transferrin, Prealbumin and Ferritin) and inflammatory (C-reactive protein, Orosomucoid) proteins were assayed in the serum before D0 and after 30 days (D30) of porridge consumption using Cobas C311 Hitachi from Roche diagnosis, France according to the method provided by the manufacturer. In terms of nutritional proteins, serum concentrations of pre-albumin or transthyretin which were below normal values on D0 with values between 0.11±0.01g/L (G1-BC1) and 0.19±0.47g /L (G4-BC4) experienced a significant increase at D30 in the groups of children who had consumed the enriched porridge (G2-BC2: 0.21±0.04g/L; G3-BC3: 0.25±0.38g/L; G4-BC4: 0.24±0.38g/L) compared to children in the control group (G1-BC1: 0.13±0.03g/L). Similarly, serum ferritin levels below normal values on D0 (G1-BC1: 49.45±7.25g/L; G2- BC2: 46.80±26.89g/L; G3-BC3: 35, 37±23.12g/L; G4-BC4: 38.18±12.81 g/L) underwent a significant increase at D30 but within the range of normal values (G1-BC1: 82.58±15.41g /l; G2-BC2: 93.90±47.20g/L; G3-BC3: 92.53±28.30g/L; G4-BC4: 100.79±28.57g/L). Albumin and transferrin concentrations remained within the normal range. As for the proteins of the inflammatory reaction, the orosomucoid concentrations on D0, which were higher than the normal value in the children of the control group (2.87±0.45g/L), of the G2-BC2 group (2. 19±0.30g/L) and in the G3-BC3 group (2.99±0.21g/L) experienced a significant drop at D30 (G1-BC1: 0.80±0.84 g/L; G2- BC2: 0.74±0.09g/L; G3-BC3: 0.71±0.38g/L. Concerning the C-reactive protein, its serum concentration remained within the limits of normal values despite its significant decrease. the values of the inflammatory and nutritional prognosis index (PINI) remained normal with values between 1 and 10 on D0 and below 1 on D30. Cashew almonds have improved the nutritional status of MAMs and reduced their risk of infection. These porridges can therefore be recommended not only for the nutritional rehabilitation of MAMs, but also for the prevention of child malnutrition.

Plasma Transthyretin Levels and Risk of Type 2 Diabetes Mellitus and Impaired Glucose Regulation in a Chinese Population.

Plasma transthyretin may be engaged in glucose regulation. We aimed to investigate the association between plasma transthyretin levels and the risk of newly diagnosed T2DM and impaired glucose regulation (IGR) in a Chinese population. We conducted a case-control study including 1244 newly diagnosed T2DM patients, 837 newly diagnosed IGR patients, and 1244 individuals with normal glucose tolerance (NGT) matched by sex and age. Multivariate logistic regression analysis was utilized to estimate the independent association of plasma transthyretin concentrations with the risk of T2DM and IGR. Plasma transthyretin concentrations were significantly higher in T2DM and IGR patients compared with control subjects (p < 0.005). After multiple adjustment and comparison with the lowest quartile of plasma transthyretin concentrations, the odds ratios (95% confidence intervals) of T2DM and IGR in the highest quartile were 2.22 (1.66, 2.98) and 2.29 (1.72, 3.05), respectively. Plasma transthyretin concentrations also showed a great performance in predicting the risk of T2DM (AUC: 0.76). Moreover, a potential nonlinear trend was observed. Our results demonstrated that higher plasma transthyretin concentrations, especially more than 290 mg/L, were associated with an increased risk of T2DM and IGR. Further studies are warranted to confirm our findings and elucidate the potential mechanisms.

Blood transthyretin for predicting immunoglobulin A vasculitis nephritis outcome in children

BackgroundIgA vasculitis is characterized by inflammation of the blood vessels, which can result in microvascular destruction and consequently renal damage. Transthyretin is a newly discovered angiogenesis regulator in promoting microvascular regeneration. This indicates that transthyretin may act as a potential predictor of IgAV as well as IgAVN. MethodsThis retrospective study included 125 patients newly diagnosed as IgAV with demographic and laboratory parameters. Of these, 78 patients had demonstrated internal organ damage and 47 patients with only skin and joint injury. Of 78 patients with organ impairment, 27 were diagnosed of renal involvement. Then we evaluated the relationship between NLR, total protein, albumin, globulin, transthyretin, B lymphocyte counts and the severity of IgAV. ResultsFor patients with internal organ or renal involvement, the level of transthyretin were lower than non-internal organ damage group (p < 0.001 for both group). Remarkably, the NLR was only higher in patients with internal organ damage group (p = 0.019). Logistic regression analysis showed that NLR and transthyretin both were risk factors for internal organ involvement (OR = 1.768, 0.973 separately), and only transthyretin is the independent risk for renal involvement (OR = 0.981, p < 0.05). The ROC analysis showed an AUC of 0.626 for NLR, 0.815 for transthyretin in predicting organ damage, 0.755 for transthyretin in patients with renal involvement (p < 0.05, to all parameters). ConclusionsTransthyretin is a better predictor in predicting internal organ or renal involvement than NLR, and low plasma transthyretin concentration can increase the risk of renal involvement in IgAV patients.

Prehabilitation intervention for patients undergoing elective colectomy

Abstract Aim: Patients with sarcopenia who undergo surgery for colorectal cancer have an increased incidence of postoperative complications and prolonged hospital stay, thus requiring prehabilitation. We evaluated the effectiveness of a prehabilitation intervention comprising exercise and nutritional therapy for patients undergoing colorectal resection. Methods: This prospective study included 44 patients undergoing colorectal resection between August 2018 and July 2019. Patients’ mean age and body mass index were 71.6 ± 10.8 years and 21.4 ± 3.4 kg/m2, respectively; 57% of the patients were female. Prehabilitation intervention comprised ≥2000 walking steps and handgrip training as exercise therapy and a postexercise 125 mL L-leucine-enriched beverage (160 kcal, 11.0 g protein, 2300 mg L-leucine) as nutritional therapy. This routine was performed preoperatively, twice a day for 10.2 ± 2.5 (7–20) consecutive days. The primary endpoint was increased skeletal mass index. The secondary endpoints were increased handgrip strength, body weight, skeletal muscle mass, body fat, and serum transthyretin concentrations. We compared patients with and without sarcopenia (sarcopenia group [SG] vs nonsarcopenia group). Results: The skeletal muscle index (before vs after intervention: 6.2 ± 1.0 vs 6.4 ± 1.0 kg/m2, P &lt; .001), body weight (52.8 ± 11.4 vs 53.5 ± 11.4 kg, P &lt; .001), skeletal muscle mass (21.1 ± 4.9 vs 21.5 ± 4.9 kg, P &lt; .001), and serum transthyretin concentration (24.6 ± 6.7 vs 26.7 ± 6.7 mg/dL, P &lt; .0001) increased after the intervention. Sub-analysis results (SG: n = 13, nonsarcopenia group: n = 30) indicated an additional increase in skeletal muscle index (P = .02) and handgrip strength (P = .02) and a further decrease in body fat ratio (P = .03) in the SG. Conclusions: Short-term prehabilitation intervention using a leucine-enriched beverage was effective in patients with sarcopenia undergoing colorectal resection. Clinical trial registry: This study was registered with the Center for Clinical Trials, Japan Medical Association at https://dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRE02_04/JMACTRE02_04.aspx?kbn=3&amp;seqno=7436 (registration no.: JMA-IIA00321).

From the Literature

From the Literature

Qualitative and semiquantitative assessment of thyroid hormone binding proteins in greyhounds and other dog breeds

Total thyroxine (T4) concentrations are lower in healthy greyhounds compared to most other non-sighthound breeds. In humans, variations in the structure or concentration of the major thyroid hormone binding proteins are responsible for most reported differences between total T4 concentrations in healthy individuals from different ethnic groups or other subpopulations. The aim of this study was to determine if such variations are also responsible for the lower total T4 concentrations in greyhounds. The predicted protein sequences of thyroxine-binding globulin (TBG), transthyretin and albumin were determined in liver tissue from a euthyroid greyhound with decreased T4 concentration and a Jack Russell terrier using reverse-transcriptase PCR. Sequences were compared to each other and online reference sequences. Serum proteins from 21 greyhounds and 21 non-sighthound dogs were separated by denaturing electrophoresis and immunoblots probed with polyclonal antibodies to human TBG and transthyretin. Reactive bands were quantified by densitrometry, expressed relative to the mean of reference samples included in each gel. Serum albumin concentrations were measured using a commercially-available assay. Several SNPs were identified but none was thought likely to explain the lower total T4 concentrations in greyhounds. There was no significant difference between the quantity of any of the binding proteins in serum from greyhounds and non-sighthound dogs. However, total T4 and transthyretin concentrations were highly correlated in the greyhound group (r = 0.73, P = 0.0002). Variation in the sequence of thyroid hormone binding proteins is not responsible for low greyhound total T4 concentrations. Further evaluation of the role of transthyretin is warranted.

Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

Several lines of evidence support low plasma transthyretin concentration as an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both ATTRm and ATTRwt cardiac amyloidosis may manifest as heart failure (HF). However, whether low plasma transthyretin concentration confers increased risk of incident HF in the general population is unknown. To evaluate whether low plasma transthyretin concentration is associated with incident HF in the general population. This study included data from 2 similar prospective cohort studies of the Danish general population, the Copenhagen General Population Study (CGPS; n = 9582) and the Copenhagen City Heart Study (CCHS; n = 7385). Using these data, first, whether low concentration of plasma transthyretin was associated with increased risk of incident HF was tested. Second, whether genetic variants in TTR associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of HF was tested. Data were collected from November 2003 to March 2017 in the CGPS and from November 1991 to June 1994 in the CCHS; participants from both studies were observed for survival time end points until March 2017. Data were analyzed from March to June 2019. Transthyretin concentration at or below the 5th percentile, between the 5th and 95th percentile (reference), and greater than the 95th percentile; genetic variants in TTR. Incident HF identified using the Danish National Patient Registry. Of 9582 individuals in the CGPS, 5077 (53.0%) were women, and the median (interquartile range [IQR]) age was 56 (47-65) years. Of 7385 individuals in the CCHS, 4452 (60.3%) were women, and the median (IQR) age was 59 (46-70) years. During a median (IQR) follow-up of 12.6 (12.3-12.9) years and 21.7 (11.6-23.8) years, 441 individuals (4.6%) in the CGPS and 1122 individuals (15.2%) in the CCHS, respectively, developed HF. Baseline plasma transthyretin concentrations at or below the 5th percentile were associated with incident HF (CGPS: hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; CCHS: HR, 1.4; 95% CI, 1.1-1.7). Risk of HF was highest in men with low transthyretin levels. Compared with p.T139M, a transthyretin-stabilizing variant, TTR genotype was associated with stepwise lower transthyretin concentrations for wild-type TTR (-16.5%), p.G26S (-18.1%), and heterozygotes for other variants (p.V142I, p.H110N, and p.D119N; -30.8%) (P for trend <.001). The corresponding HRs for incident HF were 1.14 (95% CI, 0.57-2.28), 1.29 (95% CI, 0.64-2.61), and 2.04 (95% CI, 0.54-7.67), respectively (P for trend = .04). In this study, lower plasma and genetically determined transthyretin concentrations were associated with a higher risk of incident HF, suggesting a potential mechanistic association between low transthyretin concentration as a marker of tetramer instability and incident HF in the general population.

Regression of cardiac amyloid deposits with novel therapeutics: reaching new frontiers in cardiac ATTR amyloidosis

Abstract Background Cardiac involvement is the main driver of outcome in ATTR amyloidosis. Advances in therapeutics hold potential in transforming the course of the disease but the impact on cardiac amyloid load is unknown. The aim of this study was to evaluate the impact of patisiran, a new double stranded RNA based gene silencing therapy and a stabilizer, diflunisal, on cardiac amyloid load as measured by CMR and T1 mapping, in patients with ATTR amyloidosis. Methods and results Thirty-two patients with hereditary cardiac amyloidosis were studied. Sixteen patients received treatment with patisiran, and sixteen control subjects did not receive any disease modifying treatment. Patients were assessed with echocardiogram, CMR, NT-proBNP and six-minute walk time measurements at baseline and at 1 year (Mean interval 11.45±3.08 months in treatment group, mean interval 12.82±5.06 months in the control group). CMR analysis comprised LV volumes, T1 mapping to measure the extracellular volume (ECV) occupied by amyloid, T2 mapping and late gadolinium enhancement imaging. At 1-year follow-up, there was a substantial reduction in cardiac amyloid burden, in keeping with cardiac amyloid regression in 45% of patients on treatment. Overall the treatment group showed a reduction in ECV at 1 year follow up compared to an increase in ECV at 1 year in the control group (−1.37%, 95% CI: −3.43 to 0.68% versus 5.02%, 95% CI: 2.86% to 7.18% respectively, p&amp;lt;0.001). The treatment group also showed an improvement in change in 6MWT at 1 year follow up compared to 6MWT at 1 year in the control group (−8.12 meters, 95% CI: −50.8 to 34.6 meters in the treatment group versus −132.27 meters, 95% CI: −216 to −48.6 meters in the control group, p=0.002). The treatment group showed a reduction in BNP at 1 year follow up compared to an increase in the control group (−567.87, 95% CI: −1288.90 to 153.15 in the treatment group versus 2004, 95% CI: 12.82 to 3995.45 in the control group, p&amp;lt;0.001). There was no significant difference from baseline and 1-year data between the control and treatment groups for the difference in echocardiographic parameters, native T1, T2. There was a significant reduction in the percentage of injected dose by 99Tc-DPD scintigraphy in treated patients at 1 year compared to baseline. Conclusions These findings provide the first compelling evidence of substantial cardiac amyloid regression in ATTR amyloidosis, as well as the potential for CMR to be used to track response in treated patients with ATTR cardiac amyloidosis. Combination therapy with transthyretin knock down and stabilizing agents may well be synergistic given enhanced stoichiometry of stabilizers in the face of much reduced plasma transthyretin concentration. Funding Acknowledgement Type of funding source: None

Association between transthyretin concentrations and gestational diabetes mellitus in Chinese women.

Transthyretin (TTR) is considered to be associated with insulin resistance in humans. This study aimed to investigate TTR level in gestational diabetes mellitus (GDM) and its association with glucose metabolism. Fifty pregnant women with GDM and 47 pregnant women with normal glucose tolerance matched for body mass index and age were enrolled in this study. Their blood samples were collected to detect TTR, retinol-binding protein 4 (RBP4), and their association with glucose and lipid metabolism. Serum TTR levels in the GDM group were significantly higher than those in the control group (median, 93.44 [interquartile range, 73.81, 117.79] μg/ml vs. 80.83 [74.19, 89.38] μg/ml; P = 0.006). GDM subjects had a lower RBP4/TTR ratio than the control subjects (median, 517.57 [interquartile range, 348.38, 685.27] vs. 602.56 [460.28, 730.62]; P = 0.02). The serum TTR concentrations were positively associated with neonatal weight (r = 0.223, P = 0.028), homeostatic model assessment of insulin resistance (r = 0.246, P = 0.015), and fasting blood glucose (FBG) (r = 0.363, P < 0.001). In stepwise multivariate linear regression analysis, FBG (standardized beta = 0.27, P = 0.004) and neonatal weight (standardized beta = 0.345, P < 0.001) were independent predictors of serum TTR concentrations. Additionally, FBG (standardized beta = -0.306, P = 0.002) and triglyceride (TG) (beta = 0.219, P = 0.025) were independently associated with RBP4/TTR ratio. Serum TTR concentrations were significantly higher in women with GDM than that in women without GDM, suggesting that elevated TTR level may play a role in the pathogenesis of GDM. Meanwhile, TTR was positively and independently associated with FBG and neonatal weight, while FBG and TG were independent predictors of RBP4/TTR ratio. Moreover, serum TTR levels and RBP4/TTR ratio were considered valuable markers of insulin resistance and GDM.

A More Oxidized Plasma Albumin Redox State and Lower Plasma HDL Particle Number Reflect Low-Protein Diet Ingestion in Adult Rats

Plasma albumin (ALB) redox state reflects protein nutritional status, but how it differs from other protein nutrition biomarkers remains to be fully elucidated. This study aimed to delineate the characteristics of plasma ALB redox state as a protein nutrition biomarker. Adult male Wistar rats were maintained on an AIN-93 M [14% casein, control (CT)] diet or an AIN-93 M-based 5% casein [low protein (LP)] diet ad libitum for 4 wk. Plasma samples were repeatedly obtained from the same rats at weeks 0-4, ALB redox state was determined by HPLC, and the concentrations of conventional protein nutrition biomarkers, ALB and transthyretin (TTR), were compared between the groups by Student t test. Body mass, relative muscle masses, plasma proteome, and plasma lipids at week 4 were also compared. Plasma ALB redox state shifted to a more oxidized state in the LP diet group compared with the CT diet group at weeks 1-4. The LP diet group also showed significantly lower plasma ALB concentrations at weeks 1 and 2 (13% and 11% lower, respectively) and significantly lower TTR concentration at week 1 (21% lower) compared with the CT diet group, but these concentrations did not differ significantly at weeks 3 and 4. After 4 wk, body mass and relative soleus and gastrocnemius muscle masses did not differ, but the relative plantaris muscle mass tended to be 4% lower (1.75 compared with 1.68 g/kg body mass) in the LP diet group compared with the CT group (P=0.06). The LP diet group also had a significantly lower HDL particle number than the CT group (30% lower). A more oxidized plasma ALB redox state and lower plasma HDL particle number reflect LP diet ingestion in adult rats, which did not exhibit changes of plasma ALB and TTR concentrations.

Abstract 2048: Stat3 downstream transthyretin stimulates tumor growth through regulation of tumor, immune and endothelial cells

Abstract Lung cancer is a very aggressive malignant form of cancer, and is one of the biggest public health challenges facing the United States and many other countries. Although incidence rates have been stabilized, an estimated 154,050 Americans are expected to die from lung &amp; bronchus cancer in 2018, accounting for approximately 25.3 percent of all cancer deaths. Lung cancer is a difficult disease to detect in its early stages, with greater than 50% of patients diagnosed with lung cancer presenting with metastatic disease. Early detection of lung cancer is an important opportunity for decreasing mortality while it is still treatable and curable. The overall 5-year survival rate is ~15 percent. Thus, it is essential to better understand the mechanisms that initiate lung carcinogenesis and find easy-use biomarkers for more accurate lung cancer detection. Due to heterogeneity of lung cancers, a panel of biomarkers should be used for more accurate lung cancer detection and classification. Signal transducer and activator of transcription 3 (Stat3) is well known for its lung cancer-promoting activity. To assess the consequences of STAT3 persistent activation in the lung, a doxycycline-controlled CCSP-rtTA/(tetO)7-Stat3C bitransgenic mouse model was generated that over-expresses STAT3C (a constitutively active form of STAT3) in alveolar type II (AT II) epithelial cells. In sequential steps, Stat3C over-expression up-regulated pro-inflammatory molecules, increased inflammatory cell infiltration and caused adenocarcinomas in the lung. Using this lung tumor model, thirteen secretory proteins that are Stat3 downstream gene products were identified as a panel of biomarkers for lung cancer detection in human sera. This panel of biomarkers potentially differentiates different types of lung cancer for classification. Among them, the transthyretin (TTR) concentration was highly increased in human serum of lung cancer patients. TTR concentration was also induced in the serum, bronchoalveolar lavage fluid, alveolar type II epithelial cells and alveolar myeloid cells of the CCSP-rtTA/(tetO)7-Stat3C lung tumor mouse model. Recombinant TTR stimulated lung tumor cell proliferation and growth, which were mediated by activation of mitogenic and oncogenic molecules. TTR possesses cytokine functions to stimulate myeloid cell differentiation, which are known to play roles in tumor environment. TTR demonstrated a great influence on a wide spectrum of endothelial cell functions to control tumor and immune cell migration and infiltration. TTR-treated endothelial cells suppressed T cell proliferation. Taken together, Stat3 downstream inducible secretory protein biomarkers potentially can be used as clinical targets for lung cancer personalized treatment if their expression levels are increased in a given lung cancer patient in the blood. Citation Format: Xinchun Ding. Stat3 downstream transthyretin stimulates tumor growth through regulation of tumor, immune and endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2048.

Bioimpedance phase angle is associated with serum transthyretin but not with prognostic inflammatory and nutritional index during follow-up of women submitted to bariatric surgery

Phase angle (PhA) has been used as a prognostic indicator in several clinical situations. However, the use of PhA as a prognostic tool in bariatric patients is less known. The aim of this study was to evaluate PhA as a prognostic index and its correlation with the prognostic inflammatory and nutritional index (PINI) during follow-up of women subjected to bariatric surgery. Twenty female volunteers were studied. Body weight, body mass index (BMI), PhA, and biochemical components of PINI [serum C-reactive protein, alpha-1-acid glycoprotein, albumin, and transthyretin (TTR) concentrations] were evaluated at three time points: before (T0) and approximately 2-3 (T1) and 6 (T2) months after surgery. One-way repeated measures ANOVA or the Friedman test with Tukey's post hoc test was used depending on data normality. The associations between PhA and the other parameters were evaluated using Spearman's (nonparametric data) or Pearson's (parametric data) correlation coefficient. Phase angle reduction was accompanied by a significant decrease in body weight and BMI at T1 (P<0.05), but not at T2 (P>0.05). PINI indicated low-risk complications during the preoperative period and no risk during the postoperative period (T1 and T2). No significant correlation was observed between PhA and PINI (P>0.05). Regarding its association with the biochemical components of PINI, lower PhA values were significantly correlated with lower serum TTR concentrations (r=0.633, P<0.001). Phase angle was not associated with PINI, although lower values were correlated with lower serum TTR, suggesting that PhA reduction is associated with an increased nutritional risk.

PRO59 ASSOCIATION BETWEEN CLINICAL OUTCOMES AND QUALITY OF LIFE IN PATIENTS WITH HEREDITARY TRANSTHYRETIN AMYLOIDOSIS

Hereditary transthyretin (hATTR) amyloidosis is a rare, systemic, progressive disease that often clinically manifests as polyneuropathy. The current analysis assesses associations of clinical outcomes with neuropathic-specific and generic health-related quality of life (HRQOL). Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a double-blinded, placebo-controlled randomized trial of inotersen in patients with hATTR accompanied by polyneuropathy. Clinical and patient-reported outcomes were assessed at baseline and week 66. Neuropathic-specific HRQOL was measured using the Norfolk QOL-diabetic neuropathy (DN) questionnaire, with the SF-36v2® Health Survey (SF-36v2) measuring generic HRQOL. Polyneuropathy symptoms and impairment were assessed by the polyneuropathy disability (PND) score (Stages I – IV, with higher stages indicating worse ambulatory disability), the modified Neuropathy Impairment Score+7 (mNIS+7), and the Neuropathy Symptoms and Change (NSC) questionnaire. Transthyretin (TTR) concentration was measured. Analysis of covariance models tested for differences in baseline HRQOL scores across baseline PND scores. Correlations measured associations between clinical outcomes and HRQOL measures at baseline. Ordinary least squares regression models tested associations between change-from-baseline HRQOL scores at week 66 and changes in clinical outcomes. Significantly worse scores in the majority of Norfolk QOL-DN and SF-36v2 scores were observed for patients in higher PND stages. mNIS+7 and NSC scores showed strong univariate correlations with Norfolk QOL-DN activities of daily living, large fiber neuropathy, and small fiber neuropathy domains, and SF36v2 physical functioning and role-physical domains. In multivariable regression models, decreases in NSC scores were associated with improvement in Norfolk QOL-DN domains, while decreases in both NSC scores and TTR concentration were associated with improvements in SF36v2 physical functioning and role-physical domains. Differences and changes in the severity of neuropathy predicted both neuropathic-specific and generic HRQOL. Decreased TTR concentration predicted improvement in generic HRQOL. Thus, treatments that reduce TTR and neuropathy should produce better HRQOL in patients with hATTR.