Higher Growth Differentiation Factor 15 Research Articles

Association between eating speed and atherosclerosis in relation to growth differentiation factor-15 levels in older individuals in a cross-sectional study

Although fast eating speed has been associated with cardiovascular risk factors, no studies have reported an association between fast eating speed and atherosclerosis as evaluated by carotid intima–media thickness (CIMT). Rapid glucose ingestion is known to cause glucose spikes, which may accelerate atherogenesis and increase levels of growth differentiation factor 15 (GDF-15). Therefore, GDF-15 levels may influence the association between fast eating speed and atherosclerosis. To evaluate the association between eating speed and atherosclerosis in relation to GDF-15, this cross-sectional study analyzed 742 Japanese aged 60–69 years. They were required to have normal thyroid hormone levels, because both GDF-15 levels and atherosclerosis (CIMT ≥ 1.1 mm) can be influenced by thyroid dysfunction. Participants were stratified by the median GDF-15 level. A significant positive association was observed between fast eating speed and atherosclerosis, but only among participants with a high GDF-15 level: the sex- and age-adjusted odds ratios (95% confidence intervals) were 1.95 (1.09, 3.48) in participants with a high GDF-15 level, and 0.83 (0.37, 1.88) in those with a low GDF-15 level. This association remained even after further adjustment for thyroid function and metabolic factors. Serum concentrations of GDF-15 may mediate the association between fast eating speed and atherosclerosis.

Prognostic value of growth differentiation factor-15 in heart failure among whole ejection fraction phenotypes.

The utility of growth differentiation factor-15 (GDF-15) in predicting long-term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF-15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF-15 into the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score-based model. This single-centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid-range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0years (range: 56.0-77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF-15 concentration (P=0.002) and a higher MAGGIC risk score (P<0.001). We examined the associations between GDF-15 levels and the risks of all-cause mortality and HF rehospitalization using Cox regression models. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4year follow-up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF-15 levels were significantly associated with an increased risk of all-cause mortality [hazard ratio (HR)=1.36, 95% confidence interval (CI): 1.20-1.54; P<0.001] and HF rehospitalization (HR=1.75, 95% CI: 1.57-1.95; P<0.001) across all HF phenotypes. This association remained significant when GDF-15 was treated as a categorical variable (high GDF-15 group: all-cause death: HR=1.73, 95% CI: 1.40-2.14; P<0.001; HF rehospitalization: HR=3.37, 95% CI: 2.73-4.15; P<0.001). Inclusion of GDF-15 in the MAGGIC risk score-based model provided additional prognostic value for all HF patients (Δ C-index=0.021, 95% CI: 0.002-0.041; IDI=0.011, 95% CI: 0.001-0.025; continuous NRI=0.489, 95% CI: 0.174-0.629) and HF rehospitalization (Δ C-index=0.034, 95% CI: 0.005-0.063; IDI=0.021, 95% CI: 0.007-0.032; continuous NRI=0.307, 95% CI: 0.147-0.548), particularly in the HFpEF subgroup. GDF-15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF-15 into the MAGGIC risk score-based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups.

Serum Growth Differentiation Factor 15 Levels Predict the Incidence of Frailty among Patients with Cardiometabolic Diseases

Introduction: Frailty is a crucial health issue among older adults. Growth differentiation factor 15 (GDF15) is associated with inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction, which are possible pathogeneses of frailty. However, few longitudinal studies have investigated the association between GDF15 and the incidence of frailty. Therefore, we investigated whether high serum GDF15 levels are associated with the incidence of frailty. Methods: A total of 175 older adults (mean age: 77 ± 6 years; 63% women) with cardiometabolic diseases and no frailty out of the two criteria at baseline participated. Individuals with severe renal impairment or severe cognitive impairment were excluded. Serum GDF15 levels were measured at baseline. Patients were asked to assess frailty status at baseline and annually during follow-up using the modified version of the Cardiovascular Health Study (mCHS) and the Kihon Checklist (KCL). We examined the association between GDF15 tertiles and each frailty measure during follow-up (median 38–39 months). In the multivariate Cox regression analysis, with the GDF15 tertile groups as the explanatory variables, hazard ratios (HRs) and 95% confidence intervals (CIs) for incident frailty were calculated after adjusting for covariates and using the lowest tertile group as the reference. Results: During the follow-up period, 25.6% and 34.0% of patients developed frailty, as defined by the mCHS and KCL, respectively. The highest GDF15 tertile group had a significantly higher incidence of mCHS- or KCL-defined frailty than the lowest GDF15 tertile group. Multivariate Cox regression analysis revealed that the adjusted HRs for incident mCHS- and KCL-defined frailty in the highest GDF15 tertile group were 3.9 (95% CI: 1.3–12.0) and 2.7 (95% CI: 1.1–6.9), respectively. Conclusion: High serum GDF15 levels predicted the incidence of frailty among older adults with cardiometabolic diseases and could be an effective marker of the risk for frailty in interventions aimed at preventing frailty, such as exercise and nutrition.

Analysis of growth differentiation factor-15 at the hospital stage of treatment of patients with acute myocardial infarction

Objective: to dynamically study the clinical characteristics, the level of growth differentiation factor 15 (GDF-15) during hospital treatment in patients with acute ST-segment elevation myocardial infarction (STEMI). Materials and methods: an analysis of clinical and laboratory data of STEMI patients during hospital treatment and echocardiography parameters was carried out. Scores were calculated on the GRACE scale to assess the prognosis of in-hospital mortality of patients. The characteristics of patients with STEMI were identified taking into account GDF-15 values. Statistical processing using the statistical software package "Statistica 10.0 for Windows". Results: clinical and laboratory characteristics of STEMI patients on the first day of the disease determined the prognosis. GDF-15 values increased on the first day of STEMI development and depended on the risk of in-hospital mortality on the GRACE scale. GDF-15 values tended to decrease during the inpatient phase of treatment. Patients with STEMI with a GDF-15 concentration equal to or more than 1200 ng/ml did not reach reference values in the dynamics of hospital treatment and had higher values of markers of myocardial necrosis, reflecting the impact on the prognosis. Conclusion: the GDF-15 indicator can be used as a marker for the prognosis of STEMI in combination with the GRACE scale assessment. High GDF-15 values during the hospital phase of patient treatment reflect the prognosis of STEMI patients.

Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15.

Gastric neoplasm is a high-mortality cancer worldwide. Chemoresistance is the obstacle against gastric cancer treatment. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. The mitokine growth differentiation factor 15 (GDF15) is a significant biomarker for mitochondrial disorder and is activated by the integrated stress response (ISR) pathway. The serum level of GDF15 was found to be correlated with the poor prognosis of gastric cancer patients. In this study, we found that high GDF15 protein expression might increase disease recurrence in adjuvant chemotherapy-treated gastric cancer patients. Moreover, treatment with mitochondrial inhibitors, especially oligomycin (a complex V inhibitor) and salubrinal (an ISR activator), respectively, was found to upregulate GDF15 and enhance cisplatin insensitivity of human gastric cancer cells. Mechanistically, it was found that the activating transcription factor 4-C/EBP homologous protein pathway has a crucial function in the heightened manifestation of GDF15. In addition, reactive oxygen species-activated general control nonderepressible 2 mediates the oligomycin-induced ISR, and upregulates GDF15. The GDF15-glial cell-derived neurotrophic factor family receptor a-like-ISR-cystine/glutamate transporter-enhanced glutathione production was found to be involved in cisplatin resistance. These results suggest that mitochondrial dysfunction might enhance cisplatin insensitivity through GDF15 upregulation, and targeting mitokine GDF15-ISR regulation might be a strategy against cisplatin resistance of gastric cancer.

Prognostic significance of growth differentiation factor-15 across the BMI spectrum in patients with chronic heart failure: Insights from the SUPPORT trial

Abstract Background Obesity is a risk factor for cardiovascular diseases including heart failure (HF), yet patients with obesity have better outcomes than their leaner counterparts in HF (i.e. the obesity paradox). We sought to investigate whether growth differentiation factor-15 (GDF15), an emerging biomarker in HF reflecting inflammation and oxidative stress, is a prognostic indicator across the body mass index (BMI) spectrum in chronic heart failure (CHF). Methods Serum levels of GDF15 and its prognostic significance across BMI were examined in a total of 1,040 Japanese patients with CHF enrolled in a randomized clinical trial of the SUPPORT trial (supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan) (mean age 66.0±9.9 years, 26% female). Patients were categorized into four groups: underweight (BMI &amp;lt;18.5 kg/m2; n = 56), normal (BMI 18.5-22.9; n = 304), overweight (BMI 23-24.9; n = 257), and obese (BMI ≥25; n = 423) defined based on the WHO recommendation for Asian-Pacific population. Results The underweight group consisted of older patients with a higher prevalence of NYHA class III and reduced left ventricular ejection fraction (LVEF) compared to obese patients (mean age 69.0 vs 64.7 years, NYHA class III 17.9 vs 5.9%, and mean LVEF 49.3 vs 55.5%; all p&amp;lt;0.05). Median GDF15 level in the underweight group was higher (1,864 pg/mL [IQR 1,070-2,626]) but was similar in overweight and obese groups (1,285 [953, 1772] and 1,220 [888-1,789], respectively) compared to normal BMI group (1,276 [879-2,018]). During follow-up (median 10.3 years), 540 composite events of HF hospitalization or all-cause death occurred. The risk was higher in the underweight group (adjusted HR 1.8, 95%CI [1.3-2.5]) and lower in the obesity group (adjusted HR 0.8 [95% CI 0.6-0.9]) compared to the normal BMI group. An increased GDF15 incurred a consistently higher risk from underweight to obese groups; per unit increase in logGDF15 (pg/mL) was associated with 4.1, 2.4, 1.7 and 2.4 times higher risk, respectively. The optimal cut-off point for discriminating those with and without the composite events was 1,343 pg/mL in overall patients. This cut-off value performed well as a prognostic indicator across the continuous BMI spectrum including those with higher BMI (Figure). Conclusions The prognostic significance of GDF15 persisted across the BMI spectrum in patients with CHF. GDF15 may be useful for providing prognostic information across patients with a diverse range of BMI even in those with modest outcomes.HF events in high GDF15 across BMI

Abstract 14892: Sex Difference in the Prognostic Power of Growth Differentiation Factor 15 for Cardiovascular Event: The Japan Morning Surge-Home Blood Pressure Study

Introduction: Growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, has been associated with cardiovascular event. Although previous studies have reported that there was a close association between sex hormones and GDF-15, data are sparse about sex difference in the prognostic power of GDF-15 for cardiovascular event. Hypothesis: We hypothesized that there is the differential prognostic power of GDF-15 for cardiovascular outcome according to gender. Methods: This prospective practitioner-based cohort study was conducted between 2005 and 2012 and included participants in the Japan Morning Surge-Home Blood Pressure Study with a history of at least one cardiovascular event who had GDF-15 measurements at baseline. Results: The study included 4066 participants (mean age 64.8 years; men, n=1897; women, n=2169). During an average 6.2 years follow-up, 249 cardiovascular events (coronary artery disease, stroke and heart failure) occurred. GDF-15 levels were significantly higher in the male vs. the female group (median [interquartile], 1014 [741.3-1432] ng/L vs. 909.9 [671.6-1257] ng/L; P&lt;0.001). In women, multivariate Cox analysis revealed that after adjusting other potential predictors, log-transformed GDF-15 was independently associated with cardiovascular events (Hazard ratio [HR], 2.09; 95% confidence interval [CI], 1.31-3.35; P=0.002), whereas this association was not found in men. In women, higher GDF-15 (≥1200 ng/L) was independently associated with cardiovascular event (HR, 2.23; 95%CI, 1.41-3.53; P=0.001), whereas this association was not found in men. The interaction between higher GDF-15 and cardiovascular event according to sex tended to be significant (P=0.087). Conclusions: There is a sex difference in the prognostic power of GDF-15 for cardiovascular event.

Associations of circulating GDF15 with combined cognitive frailty and depression in older adults of the MARK-AGE study.

Growth differentiation factor-15 (GDF15) might be involved in the development of cognitive frailty and depression. Therefore, we evaluated cross-sectional associations of plasma GDF15 with combined cognitive-frailty-and-depression in older (i.e. ≥ 55years) and younger adults of the MARK-AGE study. In the present work, samples and data of MARK-AGE ("European study to establish bioMARKers of human AGEing") participants (N = 2736) were analyzed. Cognitive frailty was determined by the global cognitive functioning score (GCF) and depression by the Self-Rating Depression Scale (SDS score). Adults were classified into three groups: (I) neither-cognitive-frailty-nor-depression, (II) either-cognitive-frailty-or-depression or (III) both-cognitive-frailty-and-depression. Cross-sectional associations were determined by unadjusted and by age, BMI, sex, comorbidities and hsCRP-adjusted linear and logistic regression analyses. Cognitive frailty, depression, age and GDF15 were significantly related within the whole study sample. High GDF15 levels were significantly associated with both-cognitive-frailty-and-depression (adjusted β = 0.177 [0.044-0.310], p = 0.009), and with low GCF scores and high SDS scores. High GDF15 concentrations and quartiles were significantly associated with higher odds to have both-cognitive-frailty-and-depression (adjusted odds ratio = 2.353 [1.267-4.372], p = 0.007; and adjusted odds ratio = 1.414 [1.025-1.951], p = 0.035, respectively) independent of age, BMI, sex, comorbidities and hsCRP. These associations remained significant when evaluating older adults. We conclude that plasma GDF15 concentrations are significantly associated with combinedcognitive-frailty-and-depression status and, with cognitive frailty and depressive symptoms separately in old as well as young community-dwelling adults.

Growth differentiation factor-15 and circulating biomarkers as predictors of periodontal treatment effects in patients with periodontitis: a randomized-controlled clinical trial

BackgroundDuring the last decades, in patients with periodontitis, periodontal treatment has been shown to reduce the potential release of local and systemic biomarkers linked to an early risk of systemic inflammatory disorders. This study evaluated the efficacy of non-surgical-periodontal treatment (NSPT) on growth differentiation factor 15 (GDF-15) and related circulating biomarkers such as glutathione peroxidase 1 (GPx-1), c-reactive protein (hs-CRP), and surfactant protein D (SP-D) in periodontal patients and explored whether subjects who had high GDF-15 levels at baseline showed increased clinical benefits following NSPT at 6-months follow-up.MethodsFor this two-arm, parallel randomized clinical trial, patients with periodontitis were randomly allocated to receive quadrant scaling and root-planing (Q-SRP, n = 23, median age 51 years old) or full-mouth disinfection (FMD, n = 23, median age 50 years old) treatment. Clinical and periodontal parameters were recorded in all enrolled patients. The primary outcome was to analyse serum concentrations changes of GDF-15 and of GPx-1, hs-CRP, and SP-D at baseline and at 30, 90, and 180-days follow-up after NSPT through enzyme-linked immunosorbent assay (ELISA) and nephelometric assay techniques.ResultsIn comparison with FMD, patients of the Q-SRP group showed a significant improvement in clinical periodontal parameters (p < 0.05) and a reduction in the mean levels of GDF-15 (p = 0.005), hs-CRP (p < 0.001), and SP-D (p = 0.042) and an increase of GPx-1 (p = 0.025) concentrations after 6 months of treatment. At 6 months of treatment, there was a significant association between several periodontal parameters and the mean concentrations of GDF-15, GPx-1, hs-CRP, and SP-D (p < 0.05 for all parameters). Finally, the ANOVA analysis revealed that, at 6 months after treatment, the Q-SRP treatment significantly impacted the reduction of GDF-15 (p = 0.015), SP-D (p = 0.026) and the upregulation of GPx-1 (p = 0.045).ConclusionThe results evidenced that, after 6 months of treatment, both NSPT protocols improved the periodontal parameters and analyzed biomarkers, but Q-SRP was more efficacious than the FMD approach. Moreover, patients who presented high baseline GDF-15 and SP-D levels benefited more from NSPT at 6-month follow-up.Trial registrationNCT05720481.

Associations between serum GDF15 and glycolipid metabolism disorder in metabolic associated fatty liver patients

Objective: To investigate relationships between serum growth differentiation factor 15 (GDF15) and glycolipid metabolism in patients with metabolic associated fatty liver disease (MAFLD). Methods: The current investigation was a cross-sectional study. A total of 333 patients from the Fengxian District Central Hospital were recruited into the study after physical examination from February 2020 to February 2021. There were 107 patients with MAFLD and type 2 diabetes mellitus (T2DM), including 54 males and 53 females with a mean age of (57±11) years. There were 65 patients with simple MAFLD only, including 32 men and 33 women with a mean age of (49±5) years. There were 105 patients with T2DM only, including 53 men and 52 women, with a mean age of (56±10) years. A control group of 56 people without MAFLD or diabetes,28 male, 28 female, mean age (48±6) years, was also included in the study. Serum GDF15 was measured via enzyme-linked immunosorbent assays. IBM SPSS 26.0 was used for statistical analysis. Logistic regression was used to evaluate relationships between GDF15 and metabolic abnormalities in MAFLD patients. Results: GDF15 progressively increased in the control [385 (296, 484) ng/L], nonobese MAFLD [388 (319, 435) ng/L], obese MAFLD [426 (354, 527) ng/L], T2DM [664 (483, 900) ng/L], and MAFLD+T2DM groups [770 (560, 1 074) ng/L](H=113.82, P=0.001). There was no significant difference in serum GDF15 between the simple MAFLD [406 (339, 524) ng/L] and control group (U=1 505.50, P=0.132). GDF15 was significantly higher in the MAFLD+T2DM group than in the T2DM-only group (U=4 573.50, P=0.019). In logistic regression analysis increased GDF15 was associated with increased risks of simple MAFLD [odds ratio (OR)=2.202], T2DM (OR=29.656), and MAFLD+T2DM(OR=58.197). In patients with MAFLD, serum GDF15 was higher in the FIB4 index>1.45 group [773 (534, 1 162) ng/L] than in the FIB4 index<1.45 group [527 (389, 787) ng/L] (U=1 709.50, P<0.001). Increased GDF15 was associated with an increased risk of advanced liver fibrosis (OR=2.388). Conclusion: In patients with simple MAFLD, GDF15 level was not significantly higher than in the control group. In the T2DM-only group and the MAFLD+T2DM group GDF15 was significantly higher than in the control group. Increased serum GDF15 was associated with increased risk and severity of MAFLD complicated with abnormal glucose and lipid metabolism. High GDF15 increased the risk of advanced fibrosis in MAFLD patients.

A study on the correlation of GDF15 with cancer cell invasion and poor prognosis in gallbladder cancer.

167 Background: Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily and has been found to be expressed in various human cancers. This study investigated the role of GDF15 in gallbladder cancer and its underlying molecular mechanisms. Methods: We examined immunohistochemical staining to evaluate the expression of GDF15 in 57 cases of gallbladder cancer using a tissue microarray, and clinic-pathological parameters were analyzed. In addition, we established a stable cell line overexpressing GDF15 using NOZ and OCUG-1 gallbladder cancer cell lines. The successful overexpression of GDF15 was confirmed using RT-PCR and western blot analysis. Migration and invasion assays were performed using transwell plates coated with collagen or matrigel, and cell motility was analyzed using a wound healing assay. We also performed western blot analysis to detect the expression levels of various proteins associated with cell proliferation, migration, and invasion. Results: High GDF15 expression was significantly associated with pathologic T stage ( P = 0.063), differentiation ( P = 0.062), perineal invasion ( P = 0.059) and lymphatic invasion ( P = 0.008). High GDF15 expression has also been associated with poor prognosis. Overexpression of GDF15 significantly enhanced wound healing, cell migration, invasion, and motility in comparison to controls and regulated the expression of related proteins. Our results indicate that GDF15 enhances the migratory, invasive, and motility abilities of NOZ and OCUG-1 cells in vitro and is involved in poor prognosis and overall survival of gallbladder cancer patients. Conclusions: This study implies that GDF15 could serve as a potential therapeutic target in gallbladder cancer.

Association Between Serum GDF15 Concentration and Total Mortality in Community-Dwelling Japanese Older Populations: The Involvement of Renal Dysfunction.

Serum growth differentiation factor 15 (GDF15) is associated with age-related adverse outcomes. However, renal function has not been thoroughly evaluated in studies addressing the association between GDF15 and mortality. We aimed to clarify whether GDF15 is associated with total mortality after carefully controlling renal function markers. We divided 1 801 community-dwelling Japanese older adults into quartiles according to their serum GDF15 concentrations. The correlation of GDF15 with renal function and inflammation markers was assessed by calculating Spearman correlation coefficients. Cumulative survival rates of the quartiles were estimated. In a Cox regression analysis adjusted for confounders, the association between GDF15 and mortality was evaluated. The discriminative capacity of GDF15 for the prediction of mortality was assessed with receiver-operating characteristic analysis. GDF15 was correlated with cystatin C (r = 0.394), β2-microglobulin (r = 0.382), C-reactive protein (r = 0.124), and interleukin-6 (r = 0.166). The highest GDF15 quartile showed poor survival compared to the others. Older adults with higher GDF15 were associated with an increased mortality risk, independent of demographics and clinically relevant variables (hazard ratio [95% confidence interval]: 1.98 [1.09-3.59]). This significant association disappeared when additionally adjusted for cystatin C (1.65 [0.89-3.05]) or β2-microglobulin (1.69 [0.91-3.12]). The ability to predict mortality was approximately comparable between GDF15 (area under the curve: 0.667), cystatin C (0.691), and β2-microglobulin (0.715). Serum GDF15 is associated with total mortality in older Japanese after adjustment for major confounders. The increased mortality risk in older adults with higher GDF15 may be partly attributed to decreased renal function.

The association of growth differentiation factor-15 levels and osteoporosis in patients with thalassemia

BackgroundIneffective erythropoiesis (IE) is a significant risk factor for osteoporosis in individuals with thalassemia. Growth differentiation factor-15 (GDF15), a biomarker of IE, was found to be elevated in thalassemia patients. This study aimed to examine the association between GDF15 levels and osteoporosis in patients with thalassemia. MethodsA cross-sectional study was conducted in 130 adult patients with thalassemia in Thailand. Bone mineral density (BMD) at the lumbar spine was evaluated by dual-energy X-ray absorptiometry (DXA), and with a Z-score of less than -2.0 SD was defined as osteoporosis. GDF-15 was measured using the enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to examine the associated factors with the development of osteoporosis. Receiver operator characteristic (ROC) curve analysis was used to estimate the threshold of GDF15 in predicting osteoporosis. ResultsOsteoporosis was detected in 55.4% (72/130) of the patients. Advanced age and high GDF15 levels were positively associated with osteoporosis, while an increased hemoglobin level was negatively associated with osteoporosis in patients with thalassemia. In this study, the GDF15 level's ROC demonstrated a good performance in predicting osteoporosis (AUC=0.77). ConclusionsThe prevalence of osteoporosis is high among adult thalassemia patients. Age and high GDF15 levels were significantly associated with osteoporosis in this study. A higher hemoglobin level is associated with a lower risk of osteoporosis. This study suggest that GDF15 could be used as a predictive biomarker for osteoporosis in patients with thalassemia. Adequate red blood cell transfusions and suppression of GDF15 function may be beneficial in preventing osteoporosis.

Intermittent fasting increases growth differentiation factor 15 in females with overweight or obesity but not associated with food intake

Growth differentiation factor 15 (GDF15) increases with acute fast in animals, and high GDF15 reduces food intake in rodents. We explored whether GDF15 was altered following intermittent fasting (IF) versus caloric restriction (CR), and associations with energy intake. Females with obesity received all foods at 70% (IF70 and CR70) or 100% of energy requirements for 8 weeks. IF ate 2–9% less than provided on refeeding days, resulting in greater weight losses. GDF15 was increased 5% more in IF70 versus CR70, but not associated with energy intake. This rise in GDF15 is unlikely to explain restriction of energy intake during IF.

Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer

PurposeAlthough increased plasma growth differentiation factor-15 (GDF15) levels have been reported in patients with various cancers, the predictive role of PD-1/PD-L1 inhibitors in advanced cancers remains unknown. This study aimed to investigate GDF15 levels as a predictive marker in advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors and analyze their association with immune cell populations.MethodsThis study included 87 patients with advanced NSCLC receiving anti-PD-1/PD-L1 inhibitors between March 2018 and May 2020. Blood samples were obtained immediately before and months after PD-1/PD-L1 inhibitor administration.ResultsThe objective response rate (ORR) was significantly higher in the low GDF15 than in the high GDF15 group (39.2% vs. 15.3%, P = 0.013). The median progression-free survival (PFS) was significantly longer in the low GDF15 than in the high GDF15 group (13.2 [95% CI 7.6–18.9] vs. 7.2 [95% CI 4.8–9.6] months, P = 0.048). Moreover, plasma GDF15 levels negatively correlated with PD-1+/CD8+ T cells (r = − 0.399, P = 0.003) and positively with PD-1+/Treg cells (r = 0.507, P < 0.001) and PD-1+Treg/CD4+ T cells (r = 0.439, P < 0.001). The ORR was significantly higher in the group with decreased GDF15 from baseline than in the increased GDF15 group (37.2% vs. 10.0%, P = 0.026). The median PFS was significantly longer in the decreased GDF15 group (14.8 [95% CI 10.4–19.2] vs. 5.9 [95% CI 2.8–9.0] months, P = 0.002). Plasma GDF15 levels were associated with PD-1+CD8+ T cells and PD-1+ Treg cells.ConclusionPlasma GDF15 could be a potential biomarker for predicting the efficacy and survival benefit of immunotherapy in advanced NSCLC.

Abstract 9935: Association of Hypertension and Growth Differentiation Factor 15 With Incident Coronary Heart Disease: The Kuakini Honolulu Heart Program

Introduction: Hypertension is a pathophysiological stress. Growth differentiation factor 15 (GDF15) is a stress-response protein, and a predictor for heart disease. The effects of the longevity genotype of FOXO3, a stress-response and prominent longevity-associated gene, on mortality vary in normotensive and hypertensive men. Hypothesis: The effect of GDF15 concentration on the risk of incident coronary heart disease (CHD) is different in men with different hypertension status. Methods: The Kuakini Honolulu Heart Program (KHHP) is a longitudinal study of cardiovascular diseases that started in 1965 involving 8,006 Japanese-American men in Hawaii. Proteomic analyses were performed using serum from KHHP exam 4 (1991-1993, ages 71-93) in a random sample (n=1,000) of men who in mid-life had been free of chronic diseases such as CHD, stroke, cancer, and diabetes. Participants were followed for incident CHD event (first event of MI, coronary insufficiency, angina, CABG, angioplasty, silent MI and CHD death) through December 1999. The Cox proportional hazards model was used to assess potential association of GDF15 concentration and hypertension (SBP/DBP≥160/95 mmHg or on anti-hypertensives) with incident CHD. Results: We excluded 5 men missing GDF15 data and 221 men with diseases including CHD, CHF, atrial fibrillation, LVH and stroke at baseline (KHHP exam 4). During 9 years of follow-up (median 7.92 years), 60 men developed CHD. To eliminate the possible recursive-effect of preclinical CHD on GDF15 at baseline, 6 CHD cases diagnosed within the first year of follow-up were excluded. So, there were 768 men available for analysis. Participants were divided, using tertiles of GDF15 concentration, into two groups: low-medium GDF15 (in low or middle tertile) and high GDF15 (in upper tertile). Multivariate Cox model adjusting for age, BMI, smoking (pack-years), cholesterol, HDL, diabetes and serum glucose showed a significant interaction effect of hypertension and high GDF15 on incident CHD (p=0.019); HR (95%CI) of high GDF15 vs low-medium GDF15 on CHD was 4.56 (1.51-13.76; p=0.007) in normotensive men, and 0.97 (0.49-1.92; p=0.93) in hypertensive men. Conclusions: High GDF15 concentration increases CHD risk in normotensive men, but not in hypertensive men.

Abstract 14368: Growth Differentiation Factor-15 in Heart Failure Across Body Mass Index Categories: The PREHOSP-CHF Study

Introduction: Growth differentiation factor-15 (GDF-15), a stress-responsive member of the transforming growth factor ꞵ cytokine superfamily is an independent prognostic predictor in patients with heart failure (HF). GDF-15 has been also reported to be associated with cardiac cachexia and malnutrition. However the association of GDF-15 and prognosis in patients with HF according to body mass index (BMI) is unclear. Methods: The PREHOSP-CHF study is a multicenter prospective cohort study among patients with HF. A total of 1,024 patients (mean age, 75.5 years, 58.7% male) were included in the analyses. Serum levels of GDF-15, as well as N-terminal pro brain natriuretic peptide (NT-proBNP), high sensitivity troponin I (hs-cTnI), and high sensitivity C-reactive protein (hs-CRP), were measured. We divided the patients into 3 groups based on the tertile of BMI: low (≤19.9), middle (19.9&lt;, ≤23.4), and high (&gt;23.4). Results: The low BMI group were older, and had more female, HF with preserved ejection fraction (≥50%), and NYHA 3/4. NT-proBNP levels were higher in the low group, but hs-cTnI and hs-CRP were comparable between the 3 subgroups. Median GDF-15 levels in the low, middle and high groups were 2271, 2264, and 1888 pg/ml, respectively. During 2 years follow-up, all-cause death and major adverse cardiovascular events (MACE: cardiovascular death and HF hospitalization) occurred in 111 and 130 in the low group, 66 and 132 in the middle group, and 34 and 88 in the high group. After adjustment for clinical confounders and cardiac biomarkers, higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the entire cohort. BMI subgroup analysis revealed that higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the middle and high groups, but not in the low group (Figure). Conclusions: Among HF, higher GDF-15 was significantly associated with all-cause death and MACE especially in the middle and high BMI groups.

Growth Differentiation Factor-15 as a Predictor of Functional Capacity, Frailty, and Ventricular Dysfunction in Patients With Aortic Stenosis and Preserved Left Ventricular Ejection Fraction

In aortic stenosis (AS), left ventricular (LV) remodeling often occurs before symptom onset, and early intervention may be beneficial. Risk stratification remains challenging and identification of biomarkers may be useful. We evaluated the association between growth differentiation factor-15 (GDF-15) and soluble suppression of tumorigenicity 2 (sST2) and known markers of poor prognosis in AS. Baseline plasma GDF-15 and sST2 levels were measured in 70 patients with moderate-severe AS (aortic valve area <1.5 cm2) and preserved LV ejection fraction (>45%). Patients were categorized into "low GDF-15" versus "high GDF-15" and "low sST2" versus "high sST2" groups. Groups were compared for differences in cardiovascular risk factors, 6-minute walk test, 5 m gait speed, cognitive function (Montreal Cognitive Assessment), and echocardiographic parameters. Overall, 44% of patients were deemed asymptomatic by New York Heart Association class, 61% had severe AS (aortic valve area <1 cm2) and all patients had preserved LV ejection fraction. GDF-15 levels were not predictive of AS severity. However, high GDF-15 (>1,050 pg/ml) was associated with LV dysfunction as shown by lower indexed stroke volume (p <0.01), worse LV global longitudinal strain (p=0.04), greater mean E/e' (p=0.02) and indexed left atrial volume (p <0.01). It was also associated with decreased functional capacity with shorter 6-minute walk test (p=0.01) and slower 5 m gait speed (p=0.02). Associations between sST2 levels and markers of poor prognosis were less compelling. In this study of patients with moderate to severe AS, elevated GDF-15 levels are associated with impaired functional capacity, poorer performance on fragility testing, and LV dysfunction. In conclusion, GDF-15 may integrate these markers of adverse outcomes into a single biomarker of poor prognosis.

Changes in novel cardiac extracellular matrix biomarkers in STEMI: associations with adverse outcomes

Abstract Background Ischemia-reperfusion (IR)-injury contributes to adverse outcomes following myocardial infarction undergoing reperfusion. Exaggerated remodelling of the extracellular matrix (ECM) is likely to be involved in IR-injury, potentially releasing ECM components to the systemic circulation. To improve prognostication and future therapeutic options in patients with myocardial infarction, more knowledge is warranted about ECM components associated with IR-injury. Purpose To investigate whether ECM components quantified in serum samples associate with myocardial injury and function, and clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Methods We selected biomarkers previously suggested to be involved in ECM changes in the heart, i.e. growth differentiation factor 15 (GDF-15), periostin, osteopontin, syndecan-1, syndecan-4, and bone morphogenetic protein 7. The concentrations of the biomarkers were measured in serum samples from patients with STEMI (n=239) enrolled in the POSTEMI trial, at day 1 and month 4 after hospital admission. Infarct size, microvascular obstruction (MVO), left ventricular remodelling, and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging. Major adverse cardiovascular events (MACE) and all-cause mortality were recorded after 12 months and with a median of 70 months, respectively. Results Serum levels of GDF-15, osteopontin, syndecan-1 and syndecan-4 declined, whereas periostin increased, from day 1 to month 4. Higher levels of syndecan-1 were associated with the presence of MVO (n=116) (day 1 OR 1.39 (1.06–1.82); month 4 OR 1.53 (1.08–2.17)), while higher GDF-15 and syndecan-1 were associated with the development of large infarct size (&amp;gt;75th percentile, n=57) and reduced cardiac function defined as LVEF &amp;lt;50% (n=64) at month 4. Higher levels of GDF-15 at month 4 and periostin at both time points were associated with increased risk of both MACE (n=16) (GDF-15: HR 1.42 (1.04–1.94); periostin day 1: HR 1.88 (1.09–3.25); periostin month 4: HR 1.64 (1.03–2.62)) and all-cause mortality (n=20) (GDF-15: HR 1.59 (1.28–1.97); periostin day 1: HR 1.85 (1.16–2.95); periostin month 4: HR 2.02 (1.35–3.02)) (Figure 1). On the contrary, elevated levels of syndecan-4 at month 4 were associated with lower risk of adverse outcomes, including all-cause mortality (HR 0.48 (0.28–0.84)) (Figure 1) and less IR-injury as assessed by a higher myocardial salvage index. Conclusion Elevated serum levels of GDF-15, periostin, and syndecan-1 were associated with a higher risk of adverse outcomes or detrimental remodelling in patients with STEMI. Increased levels of syndecan-4 measured 4 months after STEMI were associated with a reduced risk of all-cause mortality. Our results suggest the potential use of these biomarkers as prognostic tools and may suggest a role for these ECM components in IR injury. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health AuthorityNorwegian Health Association

The Effect of Dextrose or Protein Ingestion on Circulating Growth Differentiation Factor 15 and Appetite in Older Compared to Younger Women.

Growth differentiation factor 15 (GDF15) is a stress signal that can be induced by protein restriction and is associated with reduced food intake. Anorexia of aging, insufficient protein intake as well as high GDF15 concentrations often occur in older age, but it is unknown whether GDF15 concentrations change acutely after meal ingestion and affect appetite in older individuals. After an overnight fast, appetite was assessed in older (n = 20; 73.7 ± 6.30 years) and younger (n = 20; 25.7 ± 4.39 years) women with visual analogue scales, and concentrations of circulating GDF15 and glucagon-like peptide-1 (GLP-1) were quantified before and at 1, 2 and 4 h after ingestion of either dextrose (182 kcal) or a mixed protein-rich meal (450 kcal). In response to dextrose ingestion, appetite increased in both older and younger women, whereas GDF15 concentrations increased only in the older group. In older women, appetite response was negatively correlated with the GDF15 response (rho = −0.802, p = 0.005). Following high-protein ingestion, appetite increased in younger women, but remained low in the old, while GDF15 concentrations did not change significantly in either age group. GLP-1 concentrations did not differ between age groups or test meals. In summary, acute GDF15 response differed between older and younger women. Associations of postprandial appetite and GDF15 following dextrose ingestion in older women suggest a reduced appetite response when the GDF15 response is high, thus supporting the proposed anorectic effects of high GDF15 concentrations.