Plasma Growth Differentiation Factor 15 Levels Research Articles

Plasma GDF-15 concentration is not elevated in open-angle glaucoma.

AimRecently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease.MethodsPlasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn’s multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models.ResultsBefore correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15.ConclusionThe present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients.

Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation.

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.

Growth differentiation factor 15 (GDF-15) as potential cardiovascular risk biomarker in antiphospholipid syndrome.

An interplay between thrombo-inflammatory and atherogenic mechanisms is recognized in cardiovascular disease (CVD) pathogenesis in APS. Herein, we examine associations of growth differentiation factor-15 (GDF-15), a pro-inflammatory cytokine identified as a potent CVD risk biomarker in the general population, with subclinical atherosclerosis in APS. We measured plasma GDF-15 levels by an electrochemiluminescence immunoassay (cut-off 1200 pg/ml) and we examined carotid intima-media thickness (IMT) and the presence of carotid and femoral plaques using vascular ultrasound in 80 patients with APS (44 primary, 36 SLE/APS) and 40 healthy controls. We calculated the adjusted Global APS Score for cardiovascular disease (aGAPSSCVD), a revised adjusted Global APS Score (aGAPSS) for predicting CVD, including lupus anticoagulant, anticardiolipin and anti-beta2glycoprotein-I antibodies, and hypertension, dyslipidaemia, obesity, diabetes and smoking. GDF-15 levels were higher in APS patients vs controls, after adjusting for age and gender [absolute difference: 281 (95% CI: 141, 421) pg/ml, P < 0.001]. GDF-15 levels ≥1200 pg/ml were associated with higher mean IMT of the right and left carotid arteries [beta coefficient 0.068 (95% CI: 0.020, 0.116), P = 0.006] compared with GDF-15 levels <1200 pg/ml. GDF-15 was independently associated with mean IMT, after adjusting for gender and aGAPSSCVD [beta coefficient 0.059 (95% CI: 0.008, 0.110), P = 0.024], and additionally for statin (P = 0.025) and HCQ use (P = 0.011). GDF-15 levels ≥1200 pg/ml were associated with 2.4 times higher odds for atherosclerotic plaques (odds ratios = 2.438, 95% CI: 0.906, 6.556, P = 0.078), while this effect was reduced by including more covariates in the model. GDF-15 is independently associated with subclinical atherosclerosis in APS patients, suggesting its potential role in CVD risk stratification in APS.

Relationship between plasma growth differentiation factor-15 level and estimated glomerular filtration rate in type 2 diabetes patients with and without albuminuria.

To assess the relationship between growth differentiation factor-15 (GDF-15) levels and estimated glomerular filtration rate (eGFR) in type 2 diabetes mellitus (DM) patients with and without albuminuria. We examined 324 patients with type 2 DM in a cross-sectional study. eGFR was determined using equations from creatinine (eGFRcr) and the combination of creatinine and cystatin C (eGFRcr-cys). The patients were classified into two groups based on urinary albumin: creatinine ratio (ACR): the normoalbuminuria group (urinary ACR < 30 mg/g) and the albuminuria group (urinary ACR ≥ 30 mg/g). In individuals both with and without albuminuria, higher GDF-15 levels were associated with lower eGFRcr and eGFRcr-cys. Plasma GDF-15 levels were inversely correlated with eGFRcr in individuals both with and without albuminuria (γ = -0.624, p < 0.001 and γ = -0.509, p < 0.001, respectively). A multiple regression analysis showed that GDF-15 levels were significantly associated with eGFRcr after adjusting for age, sex and other confounders, including urinary ACR as a continuous or categorical variable (β = -0.309, p < 0.001 and β = -0.318, p < 0.001, respectively). Similarly, these results were replicated when eGFRcr-cys was considered instead of eGFRcr in correlation and regression analyses. GDF-15 levels were inversely associated with eGFR in patients with type 2 DM. This relationship was independent of albuminuria status.

Growth differentiation factor-15 is a biomarker for all-cause mortality but less evident for cardiovascular outcomes: A prospective study

Previous studies have proposed growth differentiation factor-15 (GDF-15) as a predictor of adverse cardiovascular outcomes and mortality. The present study aimed to determine if such associations remain after accounting for death as a competing risk, and if GDF-15 provides superior prediction performance than other biomarkers. Plasma GDF-15 levels and cardiovascular risk factors were measured in individuals without cardiovascular diseases (n = 4,143, aged 57.4 ± 5.96 years, 38.6 % men) from Malmö Diet and Cancer-Cardiovascular Cohort and were followed up for more than 20 years. Incidence of coronary events, ischemic stroke, cardiovascular mortality, and all-cause mortality was studied in relation to GDF-15 using Cox proportional hazards regression, with adjustment for potential confounders. Confounding from death as competing risk was carefully checked using the Fine and Gray subdistribution hazard model. Predictive capabilities were further evaluated using C-statistics, continuous net reclassification improvement, and integrated discrimination improvement. During follow-up, 424 coronary events, 327 ischemic stroke, 368 cardiovascular deaths, and 1,308 all-cause deaths occurred. After controlling for death from other causes as competing events, only all-cause mortality remained significantly related to GDF-15. The addition of GDF-15 significantly improved prediction for all-cause mortality in addition to the traditional risk factors, high-sensitive C-reactive protein and N-terminal prohormone of brain natriuretic peptide. Only N-terminal prohormone of brain natriuretic peptide improved prediction for CVD mortality. GDF-15 is a robust biomarker for all-cause mortality but less reliable for coronary event, ischemic stroke or cardiovascular mortality. Competing risk from death is an important consideration when interpreting the results.

Elevated circulating growth differentiation factor 15 is related to decreased heart rate variability in chronic kidney disease patients

Background Growth differentiation factor 15(GDF15) is a distant member of the superfamily of the transforming growth factor beta (TGF-β). It has been established that increased GDF15 levels are associated with an increased risk of cardiovascular disease. However, the detail effect of GDF15 on cardiovascular system in patients with chronic kidney disease (CKD) needs detail analysis. Methods Patients with CKD who did not need dialysis were enrolled in the study. Blood pressure (BP), endothelial function, pulse wave velocity (PWV) and heart rate variability (HRV) were taken in all subjects. Plasma GDF15 concentration was measured by an enzyme-linked immunosorbent assay. Results Among the 355 participants, the mean age was 57.4 (±14.2) years old and the mean estimated glomerular filtration rate (eGFR) was 50.1 (±33.2) mL/min/1.73m2. The average plasma GDF15 level was 1394.7 (±610.1) pg/mL. Higher GDF15 concentrations were significantly associated with decreased eGFR and increased urine protein-to-creatinine ratio (uPCR). In multivariable models, after adjusting for potential confounders, plasma GDF15 has negative concerning with HRV parameters including the standard deviation of the normal-to-normal (NN) interval (SDNN), the square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD) and Triangular Index. Conclusion We observed there was a link between increased plasma of GDF15 and decreased HRV. The mechanisms and prediction of GDF15 in the cardiovascular disease with CKD needs further discussion and study.

Plasma growth differentiation factor 15: a novel tool to detect early changes of hereditary transthyretin amyloidosis.

AimsHereditary transthyretin (ATTRv) amyloidosis is the most frequent and representative form of autosomal dominant hereditary systemic amyloidosis. Disease‐modifying treatments of the disease are more effective during the early stages, and we require biomarkers to detect early pathological changes for prompt diagnosis. This study aimed to investigate whether plasma growth differentiation factor 15 (GDF‐15) levels could aid detection of early pathological changes in ATTRv amyloidosis.Methods and resultsWe retrospectively studied 32 patients with ATTRv amyloidosis, eight asymptomatic TTR mutation carriers, and eight healthy volunteers. We evaluated plasma GDF‐15 levels in these subjects as related to levels of brain natriuretic peptide and high‐sensitivity troponin T, echocardiographic features, 99mTc‐pyrophosphate (PYP) scans, and cardiac magnetic resonance imaging findings. Plasma GDF‐15 levels significantly increased even in asymptomatic TTR mutation carriers compared with healthy volunteers (P < 0.01). Plasma GDF‐15 levels were significantly correlated with plasma brain natriuretic peptide values (P < 0.01), serum high‐sensitivity troponin T values (P < 0.05), and interventricular septal thickness at end‐diastole (P < 0.01) in patients with ATTRv amyloidosis. Plasma GDF‐15 levels in patients with PYP‐positive ATTRv amyloidosis were significantly higher than those in patients with PYP‐negative ATTRv amyloidosis (P < 0.01). Plasma GDF‐15 levels in patients with late gadolinium enhancement‐positive ATTRv amyloidosis were significantly higher than those in patients with late gadolinium enhancement‐negative ATTRv amyloidosis (P < 0.01). Groups of patients with different TTR genotypes manifested different plasma GDF‐15 levels.ConclusionsGrowth differentiation factor 15 may reflect early pathological changes of ATTRv amyloidosis.

Relationship between plasma growth differentiation factor-15 levels and diabetic retinopathy in individuals with type 2 diabetes

The purpose of our study was to investigate the relationship between plasma growth differentiation factor-15 (GDF-15) concentrations and diabetic retinopathy in patients with type 2 diabetes mellitus (DM). We evaluated 235 patients with type 2 DM in a cross-sectional study. Significantly increased levels of the plasma GDF-15 were found in individuals with diabetic retinopathy versus those without. According to the degree of diabetic retinopathy, there was a significant difference in the average plasma GDF-15 levels (no diabetic retinopathy, 1114 ng/L; nonproliferative diabetic retinopathy, 1327 ng/L; proliferative diabetic retinopathy, 1445 ng/L; p for trend = 0.035) after adjustments for confounders. Logistic regression analyses indicated that plasma GDF-15 concentrations were significantly associated with diabetic retinopathy (odds ratio per 1 standard deviation increment in the log-transformed value, 1.78; 95% confidence interval, 1.05–3.03, p = 0.032). Our study showed a significant positive relationship between plasma GDF-15 concentrations and diabetic retinopathy in type 2 DM patients.

Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer\u2019s disease in comparison with healthy aging

Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer’s disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian’ offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.

1273-P: Growth Differentiation Factor 15 (GDF15) Is Associated with Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Youth

Growth differentiation factor 15 (GDF15) has been associated with many important biological functions, such as food intake and weight regulation in response to metabolic stress. In animal models, it has also been noted that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in children. Nevertheless, the exact role of GDF15 in liver disease has yet to be elucidated. We aimed to explore the association of GDF15 with NAFLD in obese youth, and whether GDF15 changes similarly with changes in hepatic fat content (HFF%) over time. Fasting plasma GDF15 levels were measured by ELISA in obese youth with (89) and without (95) NAFLD. Additionally, fasting GDF15 levels were measured in 22 obese youth who progressed (11) or regressed (11) in HFF% by more than 30% over a two-year period. Abdominal MRI was performed on all subjects to quantify HFF%. For the first time, we describe a novel association between GDF15 and NAFLD in obese youth. Figure 1A shows a statistically significant difference in fasting GDF15 levels (p&amp;lt;0.0001) between three groups stratified by degree of HFF%. Figure 1B shows a statistically significant association between change in HFF% and change in GDF15 (p=0.01; r2=0.29). These data suggest that GDF15 levels change with change in intrahepatic fat content in obese youth and may serve as a biomarker for NAFLD in children. Disclosure B. Galuppo: None. C. Agazzi: None. B. Pierpont: None. S. Samuels: None. E. Tarabra: None. S. Caprio: None. N. Santoro: None.

GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness.

Growth differentiation factor 15 (GDF15) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether GDF15 is beneficial or detrimental. The aim of the study was to analyse the levels of circulating GDF15 in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of GDF15 was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of GDF15 increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating GDF15 is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of GDF15 plasma levels, that after the race are similar to that of patients. Moreover, GDF15 plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that GDF15 is associated with decreased muscle performance and increased inflammation.

Growth differentiation factor-15 is a prognostic marker in patients with intermediate coronary artery disease.

BackgroundGrowth differentiation factor-15 (GDF-15) is involved in multiple processes that are associated with coronary artery disease (CAD). However, little is known about the association between GDF-15 and the future ischemic events in patients with intermediate CAD. This study was conducted to investigate whether plasma GDF-15 constituted risk biomarkers for future cardiovascular events in patients with intermediate CAD.MethodsA prospective study was performed based on 541 patients with intermediate CAD (20%–70%). GDF-15 of each patient was determined in a blinded manner. The primary endpoint was major adverse cardiac event (MACE), which was defined as a composite of all-cause death, nonfatal myocardial infarction, revascularization and readmission due to angina pectoris.ResultsAfter a median follow-up of 64 months, 504 patients (93.2%) completed the follow-up. Overall, the combined endpoint of MACE appeared in 134 patients (26.6%) in the overall population: 26 patients died, 11 patients suffered a nonfatal myocardial infarction, 51 patients underwent revascularization, and 46 patients were readmitted for angina pectoris. The plasma levels of GDF-15 (median: 1172.02 vs. 965.25 pg/mL, P = 0.014) were higher in patients with ischemic events than those without events. After adjusting for traditional risk factors, higher GDF-15 levels were significantly associated with higher incidence of the composite endpoint of MACE (HR = 1.244, 95% CI: 1.048–1.478, Quartile 4 vs. Quartile 1, P = 0.013).ConclusionsThe higher level of GDF-15 was an independent predictor of long-term adverse cardiovascular events in patients with intermediate CAD.

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 &lt;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&lt;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&lt;0.001). The plasma GDF-15 level was significantly negatively correlated with the MRC-score (r = −0.60), while it was significantly positively correlated with the RFcsa loss (r = 0.18) and the % decrease in RFcsa (r = 0.16). Moreover, the RFcsa loss was significantly negatively correlated with the MRC-score (r = −0.27) (all P&lt;0.001). The ROC curve analysis showed that plasma GDF-15 level, RFcsa loss, and % decrease in RFcsa on day 7 had predictive value for ICU-AW diagnosis in mechanically ventilated patients. More specifically, the area under the ROC curve (AUC) of GDF-15 was 0.904, the AUC of RFcsa loss was 0.873, and the AUC of % decrease in RFcsa was 0.886 (all P&lt;0.001). The 90-day survival curve demonstrated that the survival rate of the high plasma GDF-15 level group was 54.00%, while that of the low plasma GDF-15 level group was 75.56%. The difference between the two groups was statistically significant (P&lt;0.05). 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.

Growth Differentiation Factor 15 in Children with Chronic Kidney Disease and after Renal Transplantation.

Growth differentiation factor 15 (GDF-15) is strongly associated with cardiovascular disease (CVD). The aim of our study was to evaluate plasma and urinary levels of GDF-15 after pediatric renal transplantation (Rtx) and in children with chronic kidney disease (CKD) and its associations to cardiovascular risk factors. In this cross-sectional study, GDF-15 was measured in plasma and urine from 53 children with a renal transplant and 83 children with CKD and related to cardiovascular risk factors (hypertension, obesity, and cholesterol) and kidney function. Forty healthy children served as a control group. Plasma levels of GDF-15 (median and range) for a Tx (transplantation) cohort, CKD cohort, and healthy controls were, respectively, 865 ng/L (463-3039 ng/L), 508 ng/L (183-3279 ng/L), and 390 ng/L (306-657 ng/L). The CKD and Tx cohorts both had significantly higher GDF-15 levels than the control group (p < 0.001). Univariate associations between GDF-15 and hyperuricemia (p < 0.001), elevated triglycerides (p = 0.028), low HDL (p = 0.038), and obesity (p = 0.028) were found. However, mGFR (p < 0.001) and hemoglobin (p < 0.001) were the only significant predictors of GDF-15 in an adjusted analysis. Urinary GDF-15/creatinine ratios were 448 ng/mmol (74–5013 ng/mmol) and 540 ng/mmol (5–14960 ng/mmol) in the Tx cohort and CKD cohort, respectively. In the CKD cohort, it was weakly correlated to mGFR (r = −0.343, p = 0.002). Plasma levels of GDF-15 are elevated in children with CKD and after Rtx. The levels were not associated with traditional cardiovascular risk factors but strongly associated with renal function.

Effect of sleeve gastrectomy on plasma growth differentiation factor-15 (GDF15) in human

BackgroundSleeve gastrostomy (SG) induces significant weight loss primarily as a result of increased satiety and reduced food intake. Growth differentiation factor-15 (GDF15) is a satiety hormone which induces a dramatic reduction of food intake and body weight. ObjectiveTo assess the effect of sleeve gastrectomy on plasma GDF 15 level and the association with the weight loss and diabetes control after SG. MethodWe assessed plasma GDF15 level in 21 patients (15 with obesity and 6 with obesity and diabetes) before and then at 1, 3 and 12 months after SG. ResultsGDF15 was significantly increased at 1 month after SG compared to before surgery level (301.9 ± 135.2 pg/ml vs 215.1 ± 119.9 pg/ml, respectively p<0.05) and increased even further at 3 months (338.86 ± 131.14 pg/ml, p<0.01) and remain elevated at 12 months (329.39 ± 152.1 pg/ml p<0.05) after SG. At 3 months after surgery, the increased GDF15 level was correlated with the magnitude of BMI loss (r2 = 0.204, p<0.05). ConclusionSG induces a significant increase in GDF15 level which is correlated with the magnitude of BMI loss.

Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice

Physical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57Bl/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.

Correlation of serum growth differentiation factor-15 level with degree of coronary artery lesion and prognosis in elderly patients with acute coronary syndrome

Objective To analyze the correlation of growth differentiation factor-15(GDF-15)level with the severity of coronary artery disease and prognosis and in elderly patients with acute coronary syndrome. Methods A total of 168 elderly patients with acute coronary syndrome admitted into Hangzhou Xixi Hospital and Shaoyifu Hospital Affiliated to Medical College of Zhejiang University from March 2017 to April 2018 were enrolled in the study.Patients were divided into three groups: GDF-15>1 800 μmol/L(n=28), GDF-15 between 1 200-1 800 μmol/L(n=45), and GDF-15<1 200 μmol/L(n=95). Plasma levels of high-sensitivity C-reactive protein(hs-CRP)and GDF-15, and SYNTAX score, single-vessel-, double-vessel, multi-vessel coronary disease and major adverse cardiovascular events(MACE)were analyzed and compared between groups. Results Plasma levels of hs-CRP and GDF-15 had significant differences among the three groups(P<0.05). There were significant statistically differences in SYNTAX score, single-vessel, double-vessel and multi-vessel coronary disease and MACE among the three groups(P<0.05). Logistic regression analysis showed that the levels of GDF-15(OR=2.092, 95%CI: 1.585~2.687), SYNTAX score(OR=1.948, 95%CI: 1.097~2.098), double-vessel lesions(OR=1.124, 95%CI: 1.006~1.251)and multi-vessel lesions(OR=1.744, 95%CI: 1.149~2.642)(all P<0.05)were statistically significant influencing factors for the prognosis. Conclusions GDF-15 level is correlated with SYNTAX score, double-vessel lesions and multi-vessel lesions, and could predict the severity of coronary artery lesions and prognosis in patients with acute coronary syndrome. Key words: Acute coronary syndrome; Growth differentiation factors; Prognosis

GROWTH DIFFERENTIATION FACTOR 15 IS CORRELATED TO MARKERS OF IMMUNOSENESCENCE IN MONOCYTES

Immunosenescence is an age-associated decrease in function of immune cells precipitated by a variety of mechanisms and affecting nearly every immune cell subset. In myeloid cell subsets, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we have described an aging effect on several functions indicating immunosenescence in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide (LPS). We hypothesized that circulating factors altered by the aging process underly these changes. Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta superfamily that has known anti-inflammatory effects in macrophages and has recently been shown to be highly differentially expressed during aging. We used biobanked serum and plasma samples to assay circulating GDF-15 levels in subjects from our previous studies and examined correlations between GDF-15 levels and monocyte mitochondrial function and inflammatory responses. Monocyte interleukin-6 production due to LPS stimulation was negatively correlated to plasma GDF-15 levels (p = 0.046). Additionally, serum GDF-15 was positively correlated to circulating CD16+ monocyte proportions (p = 0.021) and negatively correlated to monocyte mitochondrial respiratory capacity (p < 0.001). Therefore, our data suggest that GDF-15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence, and thus is an attractive candidate for therapeutic intervention to ameliorate this.

Relationship between plasma ACTA,BNP,GDF-15 and IL-6 levels and heart failure

Objective To investigate the relationship between plasma activin A(ACTA), B-type natriuretic peptide(BNP), growth differentiation factor-15 (GDF-15) and interleukin-6 (IL-6) levels and heart failure. Methods From January 2017 to December 2018, 80 patients with acute heart failure admitted to Lishui Central Hospital were selected as observation group.According to NYHA cardiac function classification, 23 patients were classified as grade II, 30 patients were classified as grade Ⅲ and 27 patients were classified as grade Ⅳ.Another 60 healthy people were selected as control group from January 2017 to December 2018.The left ventricular end-diastolic diameter(LVEDD) and left ventricular ejection fraction(LVEF) were measured by Doppler echocardiography, and the levels of ACTA, BNP, GDF-15 and IL-6 were measured by ELISA. Results The plasma ACTA[(2.43±0.54)ng/mL], BNP[(219.31±34.25)ng/L], GDF-15[(854.31±46.57)ng/L], IL-6[(183.25±39.89)ng/L]in the observation group were significantly higher than those in the control group[(0.32±0.10)ng/mL, (16.74±3.89)ng/L, (467.52±60.91)ng/L, (40.31±6.57)ng/L](t=29.859, 45.553, 42.591, 27.455, all P<0.05). The LVEDD[(65.73±5.38)mm] in the observation group was higher than that in the control group[(47.83±4.31)mm], while the LVEF[(39.82±3.56)%]was lower than that in the control group[(64.32±4.16)%](t=21.170, 37.475, all P<0.05). The ACTA[(3.98±0.58)ng/mL], BNP[(304.21±41.30)ng/L], GDF-15[(989.83±50.38)ng/L], IL-6[(249.81±45.61)ng/L] in grad Ⅳ group were lower than those in grade Ⅱ group[(1.17±0.21)ng/mL, (135.42±23.98)ng/L, (735.24±41.87)ng/L, (120.74±33.45)ng/L] and grade Ⅲ group[(2.41±0.52)ng/mL, (217.27±35.46)ng/L, (861.32±53.46)ng/L, (185.42±42.31)ng/L](F=8.391, 23.154, 17.849, 14.568, all P<0.05). The plasma levels of ACTA, BNP, GDF-15 and IL-6 in gradeⅢgroup were lower than those in grade Ⅱ group (t=10.764, 9.517, 9.322, 6.025, all P<0.05). The LVEDD[(72.31±5.91)mm]in grade Ⅳ group was higher than that in grade Ⅱ group[(58.98±4.64)mm]and grade Ⅲ group[(66.01±5.48)mm], and the LVEF[(29.97±3.36)%]was lower than that in grade Ⅱ group[(51.54±3.27)%]and grade Ⅲ group[(40.35±3.81)%], the differences were statistically significant (F=12.415, 9.829, all P<0.05). The LVEDD in grade Ⅲ group was higher than that in grade Ⅱ group, and the LVEF was lower than that in gradeⅡgroup, the differences were statistically significant(t=4.176, 10.856, all P<0.05). Conclusion The levels of ACTA, BNP, GDF-15 and IL-6 in plasma are increased in patients with acute heart failure, and are closely related to the progress of the disease.They can be used as diagnostic and prognostic indicators of acute heart failure. Key words: Heart failure; Activins; Natriuretic peptide, brain; Growth differentiation factor-15; Interleukin-6; Left ventricular end-diastolic diameter; Left ventricular ejection fraction; Cardiac function classification

Growth Differentiation Factor-15 Level and Tissue Doppler Echocardiography as a Tool in Identification of Cardiac Effects in the Children with Type 1 Diabetes Mellitus

The aim of this study was to evaluate the importance of growth-differentiation factor-15 level and tissue Doppler imaging in the detection of cardiomyopathy in children who have type 1 diabetes mellitus. Thirty-eight patients (11 males and 27 females) with type 1 diabetes mellitus were included in this study. The control group consisted of 40 age- and gender-matched healthy volunteers. All children underwent a detailed echocardiography, which contained an m-mode, pulse Doppler and tissue Doppler imaging; and growth-differentiation factor-15 level was measured. In this study, there were significant differences between diastolic function parameters of the heart. The mitral isovolumic contraction time, contraction time, and isovolumic relaxation time values were different in the patients than in the controls (p<0.01, p<0.01, p<0.01, respectively). Also, the tricuspid isovolumic contraction time, contraction time, and isovolumic relaxation time values were different in the patients than in the controls (p<0.01, p=0.01, p<0.01, respectively). No statistically significant difference was found between the other M-mode parameters. Mean plasma growth-differentiation factor-15 level was significantly higher in patients than in healthy controls (p<0.01). The follow-up of children with type 1 diabetes mellitus in terms of cardiomyopathy and the use of tissue Doppler imaging and growth differentiation factor-15 levels may be useful.