Growth differentiation factor-15 serum concentrations reflect disease severity and anemia in patients with inflammatory bowel disease.

BACKGROUND: Population of patients with inflammatory bowel disease (IBD) is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity and mortality. Growth-differentiation factor-15 (GDF-15) is often over-expressed under stress conditions, such as inflammation, malignancies, heart failure, myocardial ischemia, and many others. AIM: To explore the association between GDF-15 and IBD as serum concentrations of GDF-15 were shown to be an independent predictor of poor outcomes in multiple diseases. An additional aim was to determine possible associations between GDF-15 and multiple clinical, anthropometric and laboratory parameters in patients with IBD. METHODS: This cross-sectional study included 90 adult patients diagnosed with IBD, encompassing both Crohn's disease (CD) and ulcerative colitis (UC), and 67 healthy age- and sex-matched controls. All patients underwent an extensive workup, including colonoscopy with subsequent histopathological analysis. Disease activity was assessed by two independent gastroenterology consultants specialized in IBD, employing well-established clinical and endoscopic scoring systems. GDF-15 serum concentrations were determined following an overnight fasting, using electrochemiluminescence immunoassay. RESULTS: In patients with IBD, serum GDF-15 concentrations were significantly higher in comparison to the healthy controls [800 (512-1154) pg/mL vs 412 (407-424) pg/mL, P < 0.001], whereas no difference in GDF-15 was found between patients with CD and UC [807 (554-1451) pg/mL vs 790 (509-956) pg/mL, P = 0.324]. Moreover, multiple linear regression analysis showed that GDF-15 levels predict CD and UC severity independent of age, sex, and C-reactive protein levels (P = 0.016 and P = 0.049, respectively). Finally, an association between GDF-15 and indices of anemia was established. Specifically, negative correlations were found between GDF-15 and serum iron levels (r = -0.248, P = 0.021), as well as GDF-15 and hemoglobin (r = -0.351, P = 0.021). Accordingly, in comparison to IBD patients with normal hemoglobin levels, GDF-15 serum levels were higher in patients with anemia (1256 (502-2100) pg/mL vs 444 (412-795) pg/mL, P < 0.001). CONCLUSION: For the first time, we demonstrated that serum concentrations of GDF-15 are elevated in patients with IBD in comparison to healthy controls, and the results imply that GDF-15 might be involved in IBD pathophysiology. Yet, it remains elusive whether GDF-15 could serve as a prognostic indicator in these patients.

Proteomics validate circulating GDF-15 as an independent biomarker for COVID-19 severity.

Introduction: Growth differentiation factor 15 (GDF-15) was originally described as a stress-induced cytokine, and a biomarker of aging and cardiovascular diseases. We hypothesized that circulating GDF-15 would be associated with COVID-19 disease severity. Herein, we explored this hypothesis in a large cohort of COVID-19 patients. Methods: Blood samples were collected from 926 COVID-19 adult patients and from 285 hospitalized controls from the Biobanque Québécoise de la COVID-19 (BQC19). COVID-19 severity was graded according to the WHO criteria. SOMAscan proteomics assay was performed on 50µL of plasma. ELISA were performed on 46 selected participants with left-over plasma to validate differences in plasma GDF-15 levels. Statistical analyses were conducted using GraphPad Prism 9.0 and SPSS. P values < 0.01 were considered significant. Results: Proteomics showed that plasma GDF-15 levels were higher in COVID-19 patients compared to hospitalized controls. GDF-15 levels increased with COVID-19 severity. COVID-19 patients presenting with comorbidities including diabetes, cancer, chronic obstructive pulmonary disease (COPD) and cardiovascular disease had higher GDF-15 levels. ELISA revealed significant elevation of GDF-15 until 30 days after hospitalization. Plasma GDF-15 elevation was correlated with older age. Moreover, GDF-15 levels correlated with pro-inflammatory cytokine interleukin-6 (IL-6) and inflammation marker C-reactive protein (CRP) as well as soluble levels of its putative receptor CD48. No association was established between anti-SARS-CoV-2 IgG levels and plasma GDF-15 levels. Conclusions: This study confirms GDF-15 as a biomarker for COVID-19 severity. Clinical evaluation of GDF-15 levels could assist identification of persons at high-risk of progressing to severe disease, thus improving patient care.

Growth differentiation factor-15 as a negative predictor for microvascular obstruction in ST-segment elevation myocardial infarction after primary percutaneous coronary intervention.

Growth differentiation factor-15 (GDF-15) is an anti-inflammatory cytokine with cardioprotective effects, but circulating GDF-15 concentration predicts adverse cardiovascular outcomes in clinical settings. Microvascular obstruction (MVO) formation contributed to poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (pPCI). We aimed to investigate GDF-15 concentration in relation to cardiac magnetic resonance (CMR)-derived MVO in STEMI patients after pPCI, which might help better understand the role of GDF-15 in STEMI. GDF-15 levels at 6 h after pPCI and MVO extent at day 5 ± 2 after pPCI were measured in 74 STEMI patients (mean age 60.3 ± 12.8 years, 86.5% men). The adjusted association of GDF-15 with MVO was analyzed with MVO treated as a categorized variable (extensive MVO, defined as MVO extent ≥ 2.6% of left ventricular (LV)) and a continuous variable (MVO mass, % of LV), respectively, in multivariate logistic and linear regression models. 41.9% of the patients developed extensive MVO after pPCI. In multivariate analysis, the odds ratio (95% confidential interval (CI)) of each standard deviation (SD) increase in GDF-15 for developing extensive MVO was 0.46 (0.21, 0.82), p = 0.02). Consistently, when MVO was used a continuous variable, each SD increase in GDF-15 was associated with a substantially lower MVO mass (ß - 0.42, standard error 0.19, p = 0.03). GDF-15 was a negative predictor for MVO in STEMI patients after pPCI. The observation was consistent with results from experiment studies, suggesting a potential protective effect of GDF-15 against cardiac injury.

Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

GDF-15: a novel biomarker of heart failure predicts short-term and long-term heart-failure rehospitalization and short-term mortality in patients with acute heart failure syndrome.

BACKGROUND: Acute heart failure (AHF) is a potentially life-threatening clinical syndrome, usually requiring hospital admission. Growth Differentiation Factor-15 (GDF-15) is a distant member of the transforming growth factor-ß. The increased expression of GDF-15 has been observed during heart failure (HF) and is associated with worse outcomes. However, the relationship between GDF-15 and AHF is not well understood with limited evidence among Thai patients. PURPOSE: Investigate the correlation between biomarker levels (measured upon admission and discharge) and short- and long-term adverse outcomes, encompassing all-cause mortality and heart-failure (HF) rehospitalization (at 30, 90, and 180 days, as well as throughout the entire follow-up duration) in individuals experiencing acute HF. METHODS: This is a prospective single-center investigation involving patients admitted for AHF. Biomarkers, including GDF-15, high-sensitivity troponin T (hsTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were assessed upon admission and discharge. Outcomes, including all-cause mortality and HF rehospitalization, were examined. Logarithmic transformations were applied to the biomarker variables for subsequent analysis. Univariate and multivariate analyses of cause-specific hazards were conducted using the Cox proportional hazards regression model, while subdistribution hazards were assessed using the Fine-Gray regression model to evaluate outcomes. RESULTS: A total of 84 patients were enrolled (mean age of 69 years, 52% females). The GDF-15 level significantly decreased during admission (median at the time of admission 6,346 pg/mL, median at the time of discharge 5,711 pg/mL; p < 0.01). All-cause mortality at 30 days and 180 days were 6.0% and 16.7%, respectively. HF rehospitalization at 30 days and 180 days were 15.5% and 28.6%, respectively. Univariate analysis showed that total orthoedema congestion score (p = 0.02) and admission GDF-15 level (p = 0.01) were associated with 30-day all-cause mortality, whereas hsTnT or NT-proBNP levels did not show significant associations. However, higher levels of NT-proBNP upon admission were associated with all-cause mortality when considering the entire follow-up period (p < 0.01). Both univariate and multivariate analyses demonstrated that lower discharge GDF-15 levels and a greater reduction in GDF-15 levels from admission to discharge were associated with a lower risk of 30-day rehospitalization. Similarly, univariate analysis revealed that a greater reduction in NT-proBNP levels from admission to discharge was associated with lower 30-day rehospitalization rates. At 180 days, a greater reduction in GDF-15 levels remained associated with lower hazards and incidence of rehospitalization. CONCLUSION: The significant decrease in Growth Differentiation Factor-15 (GDF-15) levels during hospitalization suggests its potential as a dynamic marker reflecting the course of AHF. Importantly, higher GDF-15 levels at admission were associated with an increased risk of 30-day all-cause mortality, highlighting its prognostic value in this patient population. Moreover, lower discharge GDF-15 levels, reductions in GDF-15 from admission to discharge, and decreases in NT-proBNP from admission to discharge were associated with a reduced risk of 30-day rehospitalization.

The association between growth differentiation factor 15 and presence and severity of coronary atherosclerosis.

PURPOSE: Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor beta superfamily and is faintly expressed under healthy conditions. GDF-15 is markedly elevated in a variety of diseases, including coronary artery disease (CAD), atrial fibrillation and heart failure. Here, we aimed to investigate the association of GDF-15 with the extent and severity of CAD in patients with stable CAD. METHODS: We enrolled 129 patients undergoing coronary angiography for the evaluation of stable CAD in the study. SYNTAX and SYNTAX II PCI/CABG scores were calculated. The CAD (+) study group was also stratified into two groups (high and low GDF-15) with respect to the mean GDF-15 value. Correlation and regression analyses were performed for further evaluation. RESULTS: Of the 129 patients, 75 had CAD. GDF-15 values were higher in the CAD (+) group (p â€‹< â€‹0.001). The two groups were compared according to a cut-off value of 2451.77. SYNTAX and SYNTAX II PCI/CABG scores were significantly associated with the high GDF-15 group (p â€‹< â€‹0.001). Additionally, correlation analysis showed a strong positive correlation between GDF-15 and SYNTAX (r: 0.859, p â€‹< â€‹0.001), SYNTAX II PCI (r: 0.921, p â€‹< â€‹0.001) and SYNTAX II CABG (r: 0.874, p â€‹< â€‹0.001) scores. Multivariate analysis identified GDF-15 as an independent predictor of CAD. CONCLUSION: GDF-15 is an independent predictor of CAD and is associated with CAD severity in terms of SYNTAX, SYNTAX II PCI and SYNTAX II CABG scores.

Temporal biomarker concentration patterns during the early course of acute coronary syndrome.

OBJECTIVES: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. METHODS: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. RESULTS: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. CONCLUSIONS: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.

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.

Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases.

BACKGROUND: Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children. METHODS: Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls. RESULTS: GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01). CONCLUSIONS: GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.

GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

The association between growth differentiation factor-15, erythroferrone, and iron status in thalassemic patients.

BACKGROUND: Iron overload can result in grave consequences in thalassemic patients, despite the availability of iron chelators. Therefore, alternative pathways aiming to reduce iron toxicity are currently investigated. Among which, reduction of iron absorption through control of hepcidin production appears to be promising. In this study, we investigated growth differentiation factor-15 (GDF15) and erythroferrone (ERFE) as potential suppressors of hepcidin. METHODS: This cross-sectional study was conducted on 61 thalassemic patients and 60 healthy controls. The frequency of GDF15 gene polymorphism (rs4808793) (-3148C/G), serum level of GDF15 and erythroferrone were measured and correlated with those of hepcidin and serum ferritin. RESULTS: The presence of GDF15 gene mutations were significantly higher in the patients' group compared to controls (P value 0.035). Also, thalassemia patients had significantly higher levels of GDF15 and ERFE and lower hepcidin levels than controls (P value < 0.001). Serum hepcidin level showed significantly negative correlations with GDF15, ERFE, reticulocyte count, LDH level, and serum ferritin. Contrarily, it had highly significant positive correlation with hemoglobin. CONCLUSIONS: High level of GDF15 and/or ERFE may inhibit hepcidin production and increase iron load in patients with thalassemia; therefore, medications that suppress their actions may provide new therapeutic potentials for iron toxicity. IMPACT: Iron overload continues to be a major contributor to high morbidity and mortality in patients with thalassemia. New strategies together with proper chelation, need to be developed to minimize the effect of iron toxicity. Growth differentiation factor-15 (GDF15) and erythroferrone (ERFE) inhibit hepcidin production and increase iron levels in conditions with ineffective erythropoiesis. Medications that suppress the production or interfere with the action of GDF15 or ERFE may represent new therapeutic potentials for iron toxicity. Prevention of iron toxicity will significantly reduce morbidity and mortality and improve the quality of life of thalassemia patients.

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

BACKGROUND: 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. METHODS: 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. RESULTS: GDF15 was correlated with cystatin C (r = 0.394), ß2-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 ß2-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 ß2-microglobulin (0.715). CONCLUSIONS: 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.

Growth Differentiation Factor 15 and Clinical Outcomes in Japanese Patients With Heart Failure.

BACKGROUND: Heart failure (HF) is an increasing health problem associated with a high mortality rate. Growth differentiation factor (GDF) 15, a stress response cytokine belonging to the transforming growth factor-ß superfamily, is associated with poor clinical outcomes in a broad spectrum of cardiovascular diseases. However, the prognostic usefulness of GDF15 in Japanese patients with HF remains unclear.Methods and Results: We measured serum concentrations of GDF15 and B-type natriuretic peptide (BNP) in 1,201 patients with HF. All patients were prospectively followed for a median period of 1,309 days. In all, 319 HF-related events and 187 all-cause deaths occurred during the follow-up period. Kaplan-Meier analysis demonstrated that, among GDF15 tertiles, the highest tertile group had the greatest risk of HF-related events and all-cause mortality. Multivariate Cox proportional hazard regression analysis demonstrated that the serum GDF15 concentration was an independent predictor of HF-related events and all-cause deaths after adjusting for confounding risk factors. Serum GDF15 improved the prediction capacity for all-cause deaths and HF-related events with a significant net reclassification index and integrated discrimination improvement. Subgroup analysis in patients with HF with preserved ejection fraction also showed the prognostic usefulness of GDF15. CONCLUSIONS: Serum GDF15 concentrations were associated with HF severity and clinical outcomes, indicating that GDF15 could provide additional clinical information to track the health status of patients with HF.

Altered circulating GDF-15 level predicts sex hormone imbalance in males with major depressive disorder.

BACKGROUND: It has been hypothesized that higher growth differentiation factor 15 (GDF15) level and lower testosterone/ estradiol (T/E) ratio are associated with major depressive disorder (MDD), yet the underlying effect of serum GDF15 on hinting the T/E ratio imbalance is not fully understood. We observed the correlation between serum T/E ratio and circulating GDF15 in male depressed cohort. METHODS: The sample consisted of participants (aged 18 ~ 65 years) from the Renmin Hospital of Wuhan University with MDD (n = 412) defined according to a Structured Clinical Interview for DSM-V (SCID), and male healthy controls (n = 137). Serum levels of testosterone, estradiol, and depression risk biomarkers (thyroid hormone, lipids, hs-CRP, Tenascin-C [TNC], GDF15, KLF4, Gas6, and sgp130) were measured. The associations among log-transformed T/E ratio and these biomarkers were analyzed using univariate correlation analysis, category analyses, and linear regression adjusting for standard risk factors. RESULTS: Of the sample, 36.89% had lower T/E ratio (< 10:1) and 10.20% had higher T/E ratio (> 20:1). After multivariable adjustment, T/E ratio was negatively associated with GDF15 (-0.095 [95% CI -0.170 ~ -0.023] standard deviation [SD] change per SD increase in lg[T/E], P = 0.015) and inversely related to TNC (-0.085 [95% CI -0.167 ~ 0.003] standard deviation [SD] change per SD increase in lg[T/E], P = 0.048). Serum T/E ratio was negatively associated with GDF15 level in both FT3, TSH and HDL strata, whereas this association was not observed in TNC. In T/E ratio strata analyses, there is a significant and negative correlation among T/E ratio and GDF15 in depressive patients with sex hormone imbalance, yet this relationship was not investigated in patients with sex hormone balance. CONCLUSION: In our community-based observation, circulating GDF-15 level was greatly and inversely associated with serum T/E ratio, indicating that higher GDF-15 alerts sex hormone imbalance in patients with MDD.

Prognostic Value of Combined Biomarkers in Patients With Heart Failure: The Heartmarker Score.

Background: Heart failure (HF) biomarkers have prognostic value. The aim of this study was to combine HF biomarkers into an objective classification system for risk stratification of patients with HF. Methods: HF biomarkers were analyzed in a population of HF outpatients and expressed relative to their cut-off values (N-terminal pro-B-type natriuretic peptide [NT-proBNP] >1,000 pg/mL, soluble suppression of tumorigenesis-2 [ST2] >35 ng/mL, growth differentiation factor-15 [GDF-15] >2,000 pg/mL, and fibroblast growth factor-23 [FGF-23] >95.4 pg/mL). Biomarkers that remained significant in multivariable analysis were combined to devise the Heartmarker score. The performance of the Heartmarker score was compared to the widely used New York Heart Association (NYHA) classification based on symptoms during ordinary activity. Results: HF biomarkers of 245 patients were analyzed, 45 (18%) of whom experienced the composite endpoint of HF hospitalization, appropriate implantable cardioverter-defibrillator shock, or death. HF biomarkers were elevated more often in patients that reached the composite endpoint than in patients that did not reach the endpoint. NT-proBNP, ST2, and GDF-15 were independent predictors of the composite endpoint and were thus combined as the Heartmarker score. The event-free survival and distance covered in 6 minutes of walking decreased with an increasing Heartmarker score. Compared with the NYHA classification, the Heartmarker score was better at discriminating between different risk classes and had a comparable relationship to functional capacity. Conclusions: The Heartmarker score is a reproducible and intuitive model for risk stratification of outpatients with HF, using routine biomarker measurements.

Association between a Mediterranean lifestyle and growth differentiation factor 15: The seniors ENRICA-2 cohort.

BACKGROUND: Growth Differentiation Factor 15 (GDF-15) is a marker of inflammation and oxidative stress that has been associated with multiple age-related chronic diseases. Since lifestyle is key for preventing these adverse health outcomes, we examined the association between a Mediterranean lifestyle and GDF-15 serum concentrations in Spanish older adults. METHODS: We used cross-sectional data from 2502 older adults participating in the Seniors ENRICA-2 cohort. Adherence to the Mediterranean lifestyle was assessed with the 27-item MEDLIFE index, divided into three blocks: 1) "Mediterranean food consumption, 2) Mediterranean dietary habits, 3) Physical activity, rest, social habits, and conviviality". Analyses of the association between the MEFLIFE index and GDF-15 concentrations were performed using multivariable linear regression models adjusting for the main potential confounders. RESULTS: The MEDLIFE index was inversely associated with GDF-15. Compared with participants in the lowest quartile of the MEDLIFE score, GDF-15 mean percentage differences (95% CI) were -3.0% (-8.0, 2.3) for the second quartile, -8.7% (-13.0, -4.1) for the third quartile, and -10.1% (-15.0, -4.9) for the fourth quartile (p-trend<0.001). Block 3 of MEDLIFE, and particularly doing sufficient physical activity, adequate sleep duration, and participating in collective sports, was individually linked to lower concentrations of GDF-15. Results remained similar after excluding participants with cardiovascular disease, type 2 diabetes, or obesity. CONCLUSIONS: A Mediterranean lifestyle was associated with reduced levels of GDF-15, suggesting that a combination of multiple lifestyles may be an integral approach to reduce chronic inflammation and disease burden in older adults.

Association of Growth Differentiation Factor 15 with Arterial Stiffness and Endothelial Function in Subpopulations of Patients with Coronary Artery Disease: A Proof-of-Concept Study.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is a biomarker belonging to the transforming growth factor-beta cytokine superfamily, which is linked to many pathological conditions, including inflammation and myocardial injury. Pulse wave velocity (cfPWV) and augmentation index (AIx) are indices of arterial stiffness, which are associated with the severity of coronary artery disease (CAD). Flow-mediated dilatation (FMD) is a well-studied surrogate marker of endothelial-dependent dysfunction and systemic inflammation. OBJECTIVE: In this proof-of-concept study, we aimed to investigate the relationship between circulating GDF-15, endothelial dysfunction, and indices of arterial stiffness in different settings of coronary artery disease and myocardial injury. METHODS: In this cross-sectional single-center study, we enrolled patients (n = 22) after interventional treatment for acute myocardial infarction (AMI), patients (n = 11) admitted with chest pain and elevated cardiac enzymes but without evidence of obstructing CAD (MI-NOCAD) in percutaneous coronary angiography (CAG), and patients (n = 20) who underwent CAG according to indications without evident obstructive CAD in CAG (NOCAD). FMD was assessed at the brachial artery. AIx of the central aortic pressure and cfPWV were estimated by applanation tonometry at the radial and carotid-femoral site, respectively, with a validated acquisition system (Sphygmo- Cor, AtCor Medical, Sydney (NSW), Australia). ELISA was used to determine circulating GDF- 15 serum levels (R&D Systems, Minneapolis, MN). Clinical and demographic data and values of routine biochemical biomarkers were obtained. The highest high-sensitive cardiac Troponin I (hsTpnI) value during hospitalization was also recorded. Left ventricular ejection fraction (LVEF) was assessed with a transthoracic echocardiogram. RESULTS: Patients with AMI were older, had worse LVEF, higher values of hsTpnI and increased circulating GDF-15 levels. Importantly, AMI patients had increased cfPWV values, deteriorated AIx values, blunted FMD and worse serum creatinine levels compared to MI-NOCAD and NOCAD patients, respectively, whereas MI-NOCAD and NOCAD did not differ from each other significantly on these biomarkers. Both AMI and MI-NOCAD patients presented a higher but comparable white blood cell count than NOCAD patients. A strong linear correlation between GDF-15 and cfPWV, hsTpnI, AIx, white blood cell count and creatinine but not with FMD was demonstrated in the general study population. CONCLUSION: This proof-of-concept study showed that higher circulating levels of GDF-15, an inflammatory biomarker, were associated significantly with increased arterial stiffness only in AMI patients, whereas elevated GDF-15 demonstrated a linear relationship with the severity of the myocardial injury.

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.

Reference ranges for GDF-15, and risk factors associated with GDF-15, in a large general population cohort.

OBJECTIVES: Growth differentiation factor (GDF)-15 is attracting interest as a biomarker in several areas of medicine. We aimed to evaluate the reference range for GDF-15 in a general population, and to explore demographics, classical cardiovascular disease risk factors, and other cardiac biomarkers associated with GDF-15. METHODS: GDF-15 was measured in serum from 19,462 individuals in the Generation Scotland Scottish Family Health Study. Associations of cardiometabolic risk factors with GDF-15 were tested using adjusted linear regression. Among 18,507 participants with no heart disease, heart failure, or stroke, and not pregnant, reference ranges (median and 97.5th centiles) were derived by decade age bands and sex. RESULTS: Among males in the reference range population, median (97.5th centile) GDF-15 concentration at age <30 years was 537 (1,135) pg/mL, rising to 931 (2,492) pg/mL at 50-59 years, and 2,152 (5,972) pg/mL at ≥80 years. In females, median GDF-15 at age <30 years was 628 (2,195) pg/mL, 881 (2,323) pg/mL at 50-59 years, and 1847 (6,830) pg/mL at ≥80 years. Among those known to be pregnant, median GDF-15 was 19,311 pg/mL. After adjustment, GDF-15 was higher in participants with adverse cardiovascular risk factors, including current smoking (+26.1%), those with previous heart disease (+12.7%), stroke (+17.1%), heart failure (+25.3%), and particularly diabetes (+60.2%). GDF-15 had positive associations with cardiac biomarkers cardiac troponin I, cardiac troponin T, and N-terminal pro B-type natriuretic peptide (NT-proBNP). CONCLUSIONS: These data define reference ranges for GDF-15 for comparison in future studies, and identify potentially confounding risk factors and mediators to be considered in interpreting GDF-15 concentrations.

Growth Differentiation Factor-15 (GDF-15) as a Predictor of Major Adverse Cardiac Event in Acute Myocardial Infarction Patients.

BACKGROUND: Growth Differentiation Factor-15 (GDF-15) has emerged as a biomarker that capable to predicting cardiovascular events. Recent studies suggest that GDF-15 is elevated in patients with acute myocardial infarction (AMI), but the prognostic remains incompletely defined. This study aimed to investigate the role  of GDF-15 levels with major cardiac adverse events (MACE) on three months follow up in patients with AMI. METHODS: This cohort study was conducted from November 2020 until May 2021 at Dr. Moewardi Hospital. GDF-15 was measured at admission, clinical data was collected and 3 months follow up events was registered. Prognostic value of GDF-15 and hazard ratio between high and low GDF-15 level were analyzed. RESULTS: A total of 64 AMI patients were included in this study. MACE at three months follow-up occurred in 26.5% of patients. In multivariate analysis, GDF-15 was independently associated with risk of MACE at 3 months follow up (OR 1.501; p = 0.003). The cut-off point value of GDF-15 was analyzed with the ROC curve, obtained 2256 pg/mL which has a sensitivity of 94.1% and a specificity of 73.8% (area under the curve (AUC) 86.2%; 95% CI 0.768-0.956). Risk model with Kapplan Meier showed significant association between high GDF-15 levels (≥ 2256 pg/mL) and the incidence of MACE at 3 months follow up (HR 12.029; 95% CI 3.429- 42.197; p <0.001) Conclusion: In patients with AMI, high level of GDF-15 was significantly associated with the risk of MACE at 3 months of observation.