Growth Differentiation Factor 15 and Diet Quality Trajectory Interact to Determine Frailty Incidence among Middle-Aged Urban Adults.

BACKGROUND: Elevated plasma growth differentiation factor 15 (GDF15) and poor diet quality may be associated with increased frailty incidence, although their interactive associations have not been assessed in urban middle-aged adults. OBJECTIVES: We aimed to examine GDF15 and its interactive association with diet quality in relation to frailty incidence among a sample of middle-aged urban adults. METHODS: The relationship between GDF15 and diet quality trajectories in relation to incident frailty was examined in a longitudinal study of participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (2004-2017). Serum GDF15 concentration and frailty incidence were primary exposure and outcome, respectively. Group-based trajectory models were used to assess diet quality trajectories (≤3 visits/participant, N = 945, N' = 2247 observations) using the Healthy Eating Index 2010 version (HEI-2010), Dietary Inflammatory Index, and mean adequacy ratio (MAR). Cox proportional hazards models were used, testing interactive associations of GDF15 and diet quality trajectories with frail/prefrail incidence (N = 400 frailty-free at first visit, N' = 604 observations, n = 168 incident frail/prefrail). RESULTS: Both elevated GDF15 and lower diet quality trajectories were associated with a lower probability of remaining nonfrail (≤13 y follow-up). Among females, the "high diet quality" HEI-2010 trajectory had a hazard ratio (HR) of 0.15 [95% confidence interval (CI): 0.04, 0.54; P = 0.004; fully adjusted model] when compared with the "low diet quality" trajectory group. Among males only, there was an antagonistic interaction between lower HEI-2010 trajectory and elevated GDF15. Specifically, the HR for GDF15-frailty in the higher diet quality trajectory group (high/medium combined), and among males, was 2.69 (95% CI: 1.06, 6.62; P = 0.032), whereas among the lower diet quality trajectory group, the HR was 0.94 (95% CI: 0.49, 1.80; P = 0.86). Elevated GDF15 was independently associated with frailty among African American adults. CONCLUSIONS: Pending replication, we found an antagonistic interaction between GDF15 and HEI-2010 trajectory in relation to frailty incidence among males.

GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Serially measured high-sensitivity cardiac troponin T, N-terminal-pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 for risk assessment after acute coronary syndrome: the BIOMArCS cohort.

AIMS: Evidence regarding the role of serial measurements of biomarkers for risk assessment in post-acute coronary syndrome (ACS) patients is limited. The aim was to explore the prognostic value of four, serially measured biomarkers in a large, real-world cohort of post-ACS patients. METHODS AND RESULTS: BIOMArCS is a prospective, multi-centre, observational study in 844 post-ACS patients in whom 12 218 blood samples (median 17 per patient) were obtained during 1-year follow-up. The longitudinal patterns of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and growth differentiation factor 15 (GDF-15) were analysed in relation to the primary endpoint (PE) of cardiovascular mortality and recurrent ACS using multivariable joint models. Median age was 63 years, 78% were men and the PE was reached by 45 patients. The average biomarker levels were systematically higher in PE compared with PE-free patients. After adjustment for 6-month post-discharge Global Registry of Acute Coronary Events score, 1 standard deviation increase in log[hs-cTnT] was associated with a 61% increased risk of the PE [hazard ratio (HR) 1.61, 95% confidence interval (CI) 1.02-2.44, P = 0.045], while for log[GDF-15] this was 81% (HR 1.81, 95% CI 1.28-2.70, P = 0.001). These associations remained significant after multivariable adjustment, while NT-proBNP and hs-CRP were not. Furthermore, GDF-15 level showed an increasing trend prior to the PE (Structured Graphical Abstract). CONCLUSION: Longitudinally measured hs-cTnT and GDF-15 concentrations provide prognostic value in the risk assessment of clinically stabilized patients post-ACS. CLINICAL TRIAL REGISTRATION: The Netherlands Trial Register. Currently available at URL https://trialsearch.who.int/; Unique Identifiers: NTR1698 and NTR1106.

Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation.

AIMS: Cardiac functional and structural remodelling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations. METHODS AND RESULTS: ENGAGE AF-TIMI 48 was a randomized trial of edoxaban versus warfarin in 21 105 patients with AF. We performed a nested biomarker study, analysing high-sensitivity troponin T (hsTnT, n = 8705), N-terminal pro-B-type natriuretic peptide (NT-proBNP, n = 8765), and growth differentiation factor-15 (GDF-15, n = 8705) at baseline and 12 months. Of the biomarker cohort, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly reduced EF (HFmrEF; 40-49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT-proBNP, and GDF-15 were associated with higher risk of hospitalization for HF (HHF) or HF death overall and in subpopulations defined by HF history and EF (p < 0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (p-interaction >0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF or HF death in the overall population (p < 0.001 for each biomarker and category). CONCLUSION: Serial measurement of hsTnT, NT-proBNP, and GDF-15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov unique identifier NCT00781391.

Subjective assessment and biochemical evaluation of traction therapy in women with chronic low back pain: does body mass index matter? A clinical study.

BACKGROUND: Apart from the positive effect of lumbar traction on structural changes within the spine in patients with low back pain, it is likely that therapeutic effects are correlated with pain biomarkers in the blood. Among them, systemic metabolic factors related to obesity may play an important role. This is the first study designed to examine the effectiveness of traction therapy in two experimental groups with considerably different BMI and to assess relationships between blood biomarkers and low back pain intensity. METHODS: In the prospective clinical trial, women suffering from chronic low back pain were allocated into the normal-weight or obesity groups. Patients in both groups underwent twenty sessions of lumbar traction therapy (30 min a day, continuous mode with a force level of 25-30% of body weight). Before and after therapy subjective assessments of pain (VAS and PPT) were performed, and serum concentrations of aggrecan chondroitin sulfate 846 epitope (CS-846), neuropeptide Y, leptin, adipsin and growth and differentiation factor 15 (GDF-15) were determined. The data were statistically evaluated for 28 women. RESULTS: After therapy, the maximal low back pain decreased in both groups, GDF-15 concentration was reduced in the normal-weight group and increased in the obesity group, and CS-846 concentration decreased in the obesity group. The sensation of PPT in the lumbar spine and mean concentrations of neuropeptide Y, leptin and adipsin did not change in both groups. However, the relationships of GDF-15, leptin, and adipsin concentrations with the perception of pain were revealed. CONCLUSION: Distinct differences between the normal-weight and obesity groups pointed on the role of excessive adipose tissue in aggravating the inflammatory processes and in the development of low back pain. Adipsin, CS-846 and GDF-15 aspire to be the low back pain biomarkers in women with obesity, but there is a need for further research to answer whether they might be considered reliable biomarkers for the prognosis and monitoring of chronic low back treatment. TRIAL REGISTRATION: NCT04507074, registered prospectively on July 6, 2020.

Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.

Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.

Galectin-3, GDF-15, and sST2 for the assessment of disease severity and therapy response in patients suffering from inoperable chronic thromboembolic pulmonary hypertension.

PURPOSE: This study examined sST2, GDF-15, and galectin-3 as indicators of disease severity and therapy response in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This study included 57 inoperable CTEPH patients who underwent balloon pulmonary angioplasty and 25 controls without cardiovascular disease. Biomarker levels were examined in relation to advanced hemodynamic impairment [tertile with worst right atrial pressure (RAP) and cardiac index], hemodynamic therapy response [normalized hemodynamics (meanPAP ≤25 mmHg, PVR ≤3 WU and RAP ≤6 mmHg) or a reduction of meanPAP ≥25%; PVR ≥ 35%, RAP ≥25%]. RESULTS: GDF-15 [820 (556-1315) pg/ml vs. 370 (314-516) pg/ml; p < 0.001] and sST2 [53.7 (45.3-74.1) ng/ml vs. 48.7 (35.5-57.0) ng/ml; p = 0.02] were higher in CTEPH patients than in controls. At baseline, a GDF-15 level ≥1443 pg/ml (AUC 0.88; OR 31.4) and a sST2 level ≥65 ng/ml (AUC 0.80; OR 10.9) were associated with advanced hemodynamic impairment. At follow-up GDF-15 ≤ 958 pg/ml (AUC = 0.74, OR 18) identified patients with optimal hemodynamic therapy response and ≤760 pg/ml (AUC = 0.79, OR 14). CONCLUSION: GDF-15 and sST2 levels are higher in CTEPH and identified patients with advanced hemodynamic impairment. Further, decreased GDF-15 levels at follow-up were associated with hemodynamic therapy response. The diagnostic strength was not superior to NT-proBNP.

Association of Cardiac Biomarkers With the Kansas City Cardiomyopathy Questionnaire in Patients With Chronic Kidney Disease Without Heart Failure.

Background The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a measure of heart failure (HF) health status. Worse KCCQ scores are common in patients with chronic kidney disease (CKD), even without diagnosed heart failure (HF). Elevations in the cardiac biomarkers GDF-15 (growth differentiation factor-15), galectin-3, sST2 (soluble suppression of tumorigenesis-2), hsTnT (high-sensitivity troponin T), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) likely reflect subclinical HF in CKD. Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score <75 at year 1 and (2) incident decline in KCCQ score to <75. We used multivariable logistic regression and Cox regression models to evaluate the associations between baseline cardiac biomarkers and cross-sectional and longitudinal KCCQ scores. Among 2873 participants, GDF-15 (adjusted odds ratio 1.42 per SD; 99% CI, 1.19-1.68) and galectin-3 (1.28; 1.12-1.48) were significantly associated with KCCQ scores <75, whereas sST2, hsTnT, and NT-proBNP were not significantly associated with KCCQ scores <75 after multivariable adjustment. Of the 2132 participants with KCCQ ≥75 at year 1, GDF-15 (adjusted hazard ratio, 1.36 per SD; 99% CI, 1.12-1.65), hsTnT (1.20; 1.01-1.44), and NT-proBNP (1.30; 1.08-1.56) were associated with incident decline in KCCQ to <75 after multivariable adjustment, whereas galectin-3 and sST2 did not have significant associations with KCCQ decline. Conclusions Among participants with CKD without clinical HF, GDF-15, galectin-3, NT-proBNP, and hsTnT were associated with low KCCQ either at baseline or during follow-up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.

Utility of Plasma GDF-15 for Diagnosis and Prognosis Assessment of ICU-Acquired Weakness in Mechanically Ventilated Patients: Prospective Observational Study.

OBJECTIVE: To identify the clinical correlations between plasma growth differentiation factor-15 (GDF-15), skeletal muscle function, and acute muscle wasting in ICU patients with mechanical ventilation. In addition, to investigate its diagnostic value for ICU-acquired weakness (ICU-AW) and its predictive value for 90-day survival in mechanically ventilated patients. METHODS: 95 patients with acute respiratory failure, who required mechanical ventilation therapy, were randomly selected among hospitalized patients from June 2017 to January 2019. The plasma GDF-15 level was detected by ELISA, the rectus femoris cross-sectional area (RFcsa) was measured by ultrasound, and the patient's muscle strength was assessed using the British Medical Research Council (MRC) muscle strength score on day 1, day 4, and day 7. Patients were divided into an ICU-AW group and a non-ICU-AW group according to their MRC-score on the 7th day. The differences in plasma GDF-15 level, MRC-score, and RFcsa between the two groups were compared on the 1st, 4th, and 7th day after being admitted to the ICU. Then, the correlations between plasma GDF-15 level, RFcsa loss, and MRC-score on day 7 were investigated. The receiver operating characteristic curve (ROC) was used to analyze the plasma GDF-15 level, RFcsa loss, and % decrease in RFcsa on the 7th day to the diagnosis of ICU-AW in mechanically ventilated patients. Moreover, the predictive value of GDF-15 on the 90-day survival status of patients was assessed using patient survival curves. RESULTS: Based on whether the 7th day MRC-score was <48, 50 cases were included in the ICU-AW group and 45 cases in the non-ICU-AW group. The length of mechanical ventilation, ICU length of stay, and hospital length of stay were significantly longer in the ICU-AW group than in the non-ICU-AW group (all P < 0.05), while the other baseline indicators were not statistically significant between the two groups. As the treatment time increased, the plasma GDF-15 level was significantly increased, the ICU-AW group demonstrated a significant decreasing trend in the MRC-score and RFcsa, while no significant changes were found in the non-ICU-AW group. In the ICU-AW group, the plasma GDF-15 level was significantly higher than that in the non-ICU-AW group, while the RFcsa and the MRC-score were significantly lower than those in the non-ICU-AW group (GDF-15 (pg/ml): 2542.44 ± 629.38 vs. 1542.86 ± 502.86; RFcsa (cm2): 2.04 ± 0.64 vs. 2.34 ± 0.61; MRC-score: 41.22 ± 3.42 vs. 51.42 ± 2.72, all P < 0.05), while the other baseline indicators were not statistically significant between the two groups. As the treatment time increased, the plasma GDF-15 level was significantly increased, the ICU-AW group demonstrated a significant decreasing trend in the MRC-score and RFcsa, while no significant changes were found in the non-ICU-AW group. In the ICU-AW group, the plasma GDF-15 level was significantly higher than that in the non-ICU-AW group, while the RFcsa and the MRC-score were significantly lower than those in the non-ICU-AW group (GDF-15 (pg/ml): 2542.44 ± 629.38 vs. 1542.86 ± 502.86; RFcsa (cm2): 2.04 ± 0.64 vs. 2.34 ± 0.61; MRC-score: 41.22 ± 3.42 vs. 51.42 ± 2.72, all r = -0.60), while it was significantly positively correlated with the RFcsa loss (r = -0.60), while it was significantly positively correlated with the RFcsa loss (r = -0.60), while it was significantly positively correlated with the RFcsa loss (r = -0.60), while it was significantly positively correlated with the RFcsa loss (P < 0.05), while the other baseline indicators were not statistically significant between the two groups. As the treatment time increased, the plasma GDF-15 level was significantly increased, the ICU-AW group demonstrated a significant decreasing trend in the MRC-score and RFcsa, while no significant changes were found in the non-ICU-AW group. In the ICU-AW group, the plasma GDF-15 level was significantly higher than that in the non-ICU-AW group, while the RFcsa and the MRC-score were significantly lower than those in the non-ICU-AW group (GDF-15 (pg/ml): 2542.44 ± 629.38 vs. 1542.86 ± 502.86; RFcsa (cm2): 2.04 ± 0.64 vs. 2.34 ± 0.61; MRC-score: 41.22 ± 3.42 vs. 51.42 ± 2.72, all P < 0.05), while the other baseline indicators were not statistically significant between the two groups. As the treatment time increased, the plasma GDF-15 level was significantly increased, the ICU-AW group demonstrated a significant decreasing trend in the MRC-score and RFcsa, while no significant changes were found in the non-ICU-AW group. In the ICU-AW group, the plasma GDF-15 level was significantly higher than that in the non-ICU-AW group, while the RFcsa and the MRC-score were significantly lower than those in the non-ICU-AW group (GDF-15 (pg/ml): 2542.44 ± 629.38 vs. 1542.86 ± 502.86; RFcsa (cm2): 2.04 ± 0.64 vs. 2.34 ± 0.61; MRC-score: 41.22 ± 3.42 vs. 51.42 ± 2.72, all P < 0.05), while the other baseline indicators were not statistically significant between the two groups. As the treatment time increased, the plasma GDF-15 level was significantly increased, the ICU-AW group demonstrated a significant decreasing trend in the MRC-score and RFcsa, while no significant changes were found in the non-ICU-AW group. In the ICU-AW group, the plasma GDF-15 level was significantly higher than that in the non-ICU-AW group, while the RFcsa and the MRC-score were significantly lower than those in the non-ICU-AW group (GDF-15 (pg/ml): 2542.44 ± 629.38 vs. 1542.86 ± 502.86; RFcsa (cm2): 2.04 ± 0.64 vs. 2.34 ± 0.61; MRC-score: 41.22 ± 3.42 vs. 51.42 ± 2.72, all. CONCLUSION: The plasma GDF-15 concentration level was significantly associated with skeletal muscle function and muscle wasting on day 7 in ICU patients with mechanical ventilation. Therefore, it can be concluded that the plasma GDF-15 level on the 7th day has a high diagnostic yield for ICU-acquired muscle weakness, and it can predict the 90-day survival status of ICU mechanically ventilated patients.

Is proteomics of value in cardiovascular risk assessment?

PURPOSE OF REVIEW: To briefly summarize recently published evidence in the field of cardiovascular proteomics, focusing on its ability to improve cardiovascular risk stratification and critically discussing still open and burning issues and future perspectives of proteomics research. RECENT FINDINGS: Several epidemiological studies have demonstrated an improvement in cardiovascular risk prediction beyond traditional risk factors by adding novel biomarkers, identified by both discovery and targeted proteomics. However, only a moderate improvement in risk discrimination over clinical variables was observed. Moreover, despite different outcomes there was also a strong overlap of identified candidates, with several of them being already well established cardiovascular risk markers such as growth differentiation factor 15, natriuretic peptides, C-reactive protein, interleukins, and metalloproteases. SUMMARY: Although proteomics plays a crucial role in biomarker discovery, the modest discriminative ability of this technique raises the possibility that there are still hidden mechanisms in protein regulatory networks, which urgently need to be evaluated to improve a cardiovascular risk assessment to a clinically significant extent.

Association of growth differentiation factor 15 with other key biomarkers, functional parameters and mortality in community-dwelling older adults.

BACKGROUND: Growth differentiation factor 15 (GDF-15) has been associated with many adverse age-related outcomes and other age-related disorders. The aim of the study was to investigate if baseline levels of GDF-15 are associated with total mortality in community living, older adults during eight years of follow-up after simultaneous consideration of key biomarkers and functional parameters. METHODS: prospective cohort study including 1,470 community-dwelling older adults aged 65 years or older. GDF-15 was measured by ElectroChemi-Lumisnescence Immunoassays (Roche, Mannheim, Germany). We used Cox-proportional hazards regression to estimate the association of GDF-15 levels with 8-year all-cause mortality. RESULTS: GDF-15 levels were independently of age and sex strongly associated with many biomarkers such as CRP, IL-6, NT-proBNP, hs-troponines as well as with lipids, metabolic and endocrine markers and kidney function (all P-values < 0.001). GDF-15 showed also a statistically significant correlation to gait speed, hand grip strength and walking duration. In addition, we found a consistent association between levels of GDF-15 and risk of subsequent all-cause mortality which persisted after additional adjustment for key markers of inflammation, cardiac function and damage, and physical function. The hazard ratio (HR) per unit increase of log-transformed GDF-15 was 1.72 (95% CI 1.35; 2.18). CONCLUSIONS: GDF-15 levels were not only strongly associated with many functional parameters and key biomarkers independently of age and sex, but also with 8-year all-cause mortality even after adjusting for gait speed, NT-proBNP and hs-TnT.

An Assessment of Novel Biomarkers in Bone Metastatic Disease Using Multiplex Measurement and Multivariate Analysis.

AIM: Current diagnostics of bone metastatic disease is not satisfactory for early detection or regular process monitoring. The combination of biomarkers and the multiparametric approach was described as effective in other oncology diagnoses. The aim of the study was to improve the difference diagnostics between bone-metastatic disease and solid tumors using mutivariate logistic regression model. METHODS: We assessed the group of 131 patients with the following diagnoses: prostate cancer, breast cancer, lung cancer, and colorectal cancer. According to the results of scintigraphy, the cohort was divided into 2 groups based on the occurrence of bone metastases. Group 0 was a control group of 75 patients with no signs of bone metastases and group 1 included 56 patients with bone metastases. RESULTS: We used stepwise selection multivariate logistic regression for choosing the multimarker formula for calculation of risk score for bone metastases diagnostics. For detection of bone metastasis, it was shown to be most effective measurement of 3 biomarkers: procollagen type 1 N-terminal propeptide, growth differentiation factor-15, and osteonectin and combining with calculation of risk score by designating measured concentrations in mathematical formula: bone risk score = procollagen type 1 N-terminal propeptide × 0.0500 + growth differentiation factor-15 × 1.4179 + osteonectin × 0.00555. CONCLUSION: We identified growth differentiation factor-15 as the best individual marker for bone metastasis diagnostics. The best formula for risk score includes levels of 3 biomarkers-procollagen type 1 N-terminal propeptide, growth differentiation factor-15, and osteonectin. The new score has better performance described by higher area under the curve than individual biomarkers. A further study is necessary to confirm these findings incorporating a larger number of patients.

Are Markers of Cardiac Dysfunction Useful in the Assessment of Cardiovascular Risk in Dialysis Patients?

BACKGROUND: Cardiovascular morbidity and mortality of dialysis patients are major problems in this group of patients. METHODS: The purpose of this study was also to evaluate whether any of the studied markers are better than troponin in early detection of the occurrence of ventricular arrhythmias and prolongation of QT interval. This study included 45 patients undergoing hemodialysis. ECG Holter and echocardiographic examination were performed before and after dialysis. The concentrations of markers: copeptin, GDF-15, HFABP and troponin were measured with the use of ELISA tests. RESULTS: We observed significantly higher QT (p=0.004), QTc (0.018), right atrium volume (p=0.006) and concentrations of copeptin (p<0.0001) and H-FABP (p<0.0001) as well as smaller left atrium volume (p<0.0001) and width of inferior vena cava (p<0.0001) after dialysis than before it. Significantly longer QT and higher copeptin levels were seen in patients with ventricular arrhythmia. A trend between the increase in copeptin concentration and H-FABP level and the presence of ventricular arrhythmias was also noted. CONCLUSION: Generally, we failed to find any strong predictor of post-dialysis ventricular arrhythmia or the prolongation of QT, however, it seems that copeptin may have prognostic value, but this has to be analyzed in large studies.

The Expression of GDF-15 in the Human Vitreous in the Presence of Retinal Pathologies with an Inflammatory Component.

PURPOSE: The presence of growth differentiation factor-15 (GDF-15), a protein implicated in the regulation of the inflammatory response, was investigated in the vitreous of patients with vitreoretinal disorders. METHODS: Vitreous and plasma samples were collected from patients with idiopathic epiretinal membrane (IERM), macular hole (MH), rhegmatogenous retinal detachment (RRD), nucleus drop (ND), or proliferative diabetic retinopathy (PDR). GDF-15 concentrations were measured using ELISA. RESULTS: The vitreous levels of GDF-15 were higher in ND (5) and PDR (14) patients (1494 ± 243 and 904 ± 138 pg/mL, respectively) than RRD (3), MH (3), and IERM (8) patients (302 ± 160, 288 ± 24, and 254 ± 91 pg/mL, respectively). The vitreous levels of GDF-15 were significantly higher in patients with inflammatory vitreoretinal disorders (p < 0.0001). CONCLUSIONS: This is the first report showing that GDF-15 appears to be expressed in the vitreous, and that its expression is significantly higher in the presence of a vitreoretinal disorder in which there is an inflammatory component.

No Added Value of Novel Biomarkers in the Diagnostic Assessment of Patients Suspected of Acute Coronary Syndrome.

BACKGROUND: Despite the availability of high-sensitive troponin (hs-cTnT), there is still room for improvement in the diagnostic assessment of patients suspected of acute coronary syndrome (ACS). Apart from serial biomarker testing, which is time-consuming, novel biomarkers like copeptin have been proposed to expedite the early diagnosis of suspected ACS in addition to hs-cTnT. We determined whether placenta derived growth factor (PlGF), soluble Fms-like tyrosine kinase 1 (sFlt-1), myoglobin, N-terminal prohormone B-type Natriuretic Peptide (NT-proBNP), growth-differentiation factor 15 (GDF-15) and copeptin improved early assessment of chest pain patients. METHODS: This prospective, single centre diagnostic FAME-ER study included patients presenting to the ED with symptoms suggestive of ACS. Blood was collected to measure biomarkers, notably, hs-cTnT was retrospectively assessed. Added value of markers was judged by increase in AUC using multivariable logistic regression. RESULTS: Of 453 patients enrolled, 149 (33%) received a final diagnosis of ACS. Hs-cTnT had the highest diagnostic value in both univariable and multivariable analysis. PPVs of the biomarkers ranged from 23.5% (PlGF) to 77.9% (hs-cTnT), NPVs from 67.0% (PlGF) to 86.4% (hs-cTnT). Only myoglobin yielded diagnostic value in addition to clinical symptoms and electrocardiography (ECG) (AUC of clinical model 0.80) with AUC of 0.84 (p<0.001). However, addition of hs-cTnT was superior (AUC 0.89, p<0.001). Addition of the biomarkers to our clinical model and hs-cTnT did not or only marginally (GDF-15) improved diagnostic performance. CONCLUSION: When assessing patients suspected of ACS, only myoglobin had added diagnostic value beyond clinical symptoms and ECG. However, when combined with hs-cTnT, it yields no additional diagnostic value. PlGF, sFlt-1, NT-proBNP, GDF-15 and copeptin had no added value to the clinical model or hs-cTnT.

Personalized risk assessment of heart failure patients: more perspectives from transforming growth factor super-family members.

More personalized risk assessment of patients with heart failure (HF) is important to develop more tailored based care and for a better allocation of resources. The measurement of biomarkers is now part of the standards of care and is important for the sub-phenotyping of HF patients to demonstrate the activation of pathophysiological pathways engaged in the worsening of HF. The sub-phenotyping of patients can lead therefore to a more personalized selection of the treatment. Several members of the transforming growth factor ß (TGF-ß) super-family, such as myostatin, activin A, GDF-15 and GDF-11, are involved in cardiac remodeling and the evaluation of their circulating levels might provide new insights to the course of the disease and also to guide prognostication and therapeutic selection of HF patients.

Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

BACKGROUND: Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. METHODS AND RESULTS: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977-2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. CONCLUSIONS: GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

The role of cardiac biomarkers in cardiovascular disease risk assessment.

PURPOSE OF REVIEW: A range of cardiovascular biomarkers have come into the routine clinical use for the diagnosis and assessment of patients with symptomatic coronary disease. The review will consider the current evidence base for the role of measurement of a number of these biomarkers in asymptomatic patients. RECENT FINDINGS: Measurement of the cardiac troponins, cardiac troponin T and cardiac troponin I, using sensitive methods, defines a true reference population, and has demonstrated risk of cardiovascular events with small elevations above the reference interval and a gradient of risk across the reference range even in normal healthy individuals. Similar results can be seen for the measurement of the ventricular stress marker B-type natriuretic peptide. In an asymptomatic population, there is occult cardiovascular disease which can be detected by cardiovascular biomarker measurement. Novel markers of myocardial inflammation and fibrosis, such as growth differentiation factor 15, are also powerful predictors of mortality. Measurement of these cardiovascular biomarkers provides additional risk prediction when added to risk prediction models based on the conventional risk factors. SUMMARY: The measurement of cardiovascular biomarkers has the potential to provide additional risk stratification beyond conventional risk factors. The challenge is to translate biomarker measurements to treatment strategies which will reduce long-term cardiovascular risk.

Plasma MIC-1 and PAPP-a levels are decreased among women presenting to an early pregnancy assessment unit, have fetal viability confirmed but later miscarry.

BACKGROUND: We have recently shown first trimester Macrophage inhibitory cytokine-1 (MIC-1) and Pregnancy Associated Plasma Protein-A (PAPP-A) serum concentrations are depressed among asymptomatic women destined to miscarry. Here we examined whether plasma levels of MIC-1 and PAPP-A are depressed among women presenting to an Early Pregnancy Assessment Unit (EPAU), noted to have a confirmed viable fetus, but subsequently miscarry. METHODS: We performed a prospective cohort study, recruiting 462 women in the first trimester presenting to EPAU and had fetal viability confirmed by ultrasound. We obtained plasma samples on the same day and measured MIC-1, PAPP-A and human chorionic gonadotrophin (hCG), grouping the cohort according to whether they later miscarried or not. To correct for changes in analyte levels across gestation, we expressed the data as Multiples of the normal Median (MoMs). RESULTS: We recruited 462 participants presenting to EPAU at 5-12 weeks gestation. Most (80%) presented with symptoms of threatened miscarriage (e.g. abdominal pain, vaginal bleeding). 34 (7.4%) subsequently miscarried. Median plasma MIC-1 levels among those who miscarried were 50% of those with ongoing pregnancies (Miscarriage cohort MoM 0.50 (25(th)-75(th) centiles: 0.29-1.33) vs ongoing pregnancies MoM 1.00 (0.65-1.38); p=0.0025). Median plasma PAPP-A MoMs among those who miscarried was 0.57 (0.00-1.12), significantly lower than those with ongoing pregnancies (MoMs 1.00 (0.59-1.59); p=0.036). Plasma hCG levels were also significantly depressed among those who miscarried compared to those with ongoing pregnancies. However, the performance of MIC-1 as a diagnostic marker to predict miscarriage in this cohort was modest, and not improved with the addition of hCG. CONCLUSION: MIC-1 and PAPP-A levels are significantly depressed in women presenting to EPAU with ultrasound evidence of fetal viability, but later miscarry. While they are unlikely to be useful as predictive biomarkers in this clinical setting, they probably play important roles in the maintenance of early pregnancy.