Serum Growth Differentiation Factor 15 Levels Research Articles

Growth differentiation factor-15 as a modulator of bone and muscle metabolism.

This study aims to clarify the potential role of growth differentiation factor-15 (GDF-15) as a myokine in bone metabolism and muscle function in females with osteoporosis. In total, 45 female participants (71.0 ± 8.5 years) with distal radius fractures were recruited. Participants were classified as healthy/osteopenic (n=28) (CON) or osteoporotic (n=17) (OP) according to their T-score from the areal bone mineral density (aBMD) of the femoral neck. Body mass index, upper arm and calf circumferences, and handgrip strength were assessed. Total hip, femoral neck, and lumbar spine aBMD was measured via dual-energy x-ray absorptiometry. The focal bone quality of the distal radius was evaluated via 3D reconstructed computed tomographic images. Serum levels of GDF-15, insulin-like growth factor-1, and inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-1β (IL-1β), as well as the corresponding mRNA levels in the pronator quadratus muscle were determined. Participants in the OP group had higher serum GDF-15 levels than those in the CON group. The mRNA levels of GDF-15, IL-1β, and TNF-α in the pronator quadratus muscle were significantly higher in the OP group than in the CON one. Levels of both serum GDF-15 and GDF-15 mRNA in muscle were positively correlated with age and negatively associated with the aBMD of the total hip and focal bone quality of the distal radius. Handgrip power was not correlated with circulating GDF-15 levels but was correlated with circumferences of the upper arm and calf, and levels of GDF-15 mRNA in muscle specimens. The mRNA levels of GDF-15 were correlated with those of inflammatory cytokines such as TNF-α and IL-1β. The mRNA levels of TNF-α were associated with circumferences of the upper arm and calf and with the aBMD of the total hip. The mRNA levels of GDF-15 in muscle were correlated with serum levels of GDF-15 and TNF-α. GDF-15 may have associations with bone metabolism in humans via paracrinological and endocrinological mechanisms. Maintenance of muscle mass and function would be influenced more by GDF-15 in muscle than by circulating GDF-15. The role of GDF-15 in bone metabolism and muscle homeostasis could be related to inflammatory responses.

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 (>75th percentile, n=57) and reduced cardiac function defined as LVEF <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

Serum growth differentiation factor 15 levels as a marker for liver cirrhosis and hepatocellular carcinoma on top of liver cirrhosis

Background Cirrhosis is the 14th leading cause of mortality globally. Additionally, it is subclassified by clinical stage. Hepatocellular carcinoma (HCC) was reported to account for ~4.7% of patients with chronic liver disease in Egypt. Early detection and treatment are highly beneficial. Growth differentiation factor 15 (GDF-15) proteins are implicated in the infection, fibrosis, and apoptotic processes of the liver. GDF-15 mRNA is mostly found in the heart, kidney, and lungs, as well as in the liver. The adult liver expresses the greatest amounts of GDF-15 following surgical and pharmacological therapies that produce acute liver damage. Aim This study’s objective was to assess serum GDF-15 levels in individuals with cirrhosis of the liver and HCC on top of cirrhosis of the liver. Patients and methods We have recruited 90 people in three groups: group 1 comprised 35 patients with HCC, group 2 comprised 35 individuals having cirrhosis of the liver, and group 3 comprised 20 nonhepatic individuals who acted as controls. Results In the HCC group, alpha-fetoprotein (AFP) was significantly higher than in the cirrhosis group, and the cirrhosis group has significantly higher AFP than in the control group. In comparison with the cirrhosis group, and in comparison with the control group, the HCC group had a significant increase in GDF-15 level. Conclusions GDF-15 levels were substantially greater in individuals with HCC compared with patients with cirrhosis and healthy controls. It is more sensitive, specific, and accurate than AFP. Thus, we may regard GDF-15 as a new marker for the diagnosis of HCC.

Late-Life Depression is Associated With Increased Levels of GDF-15, a Pro-Aging Mitokine

ObjectiveIn older adults, major depressive disorder (MDD) is associated with accelerated physiological and cognitive aging, generating interest in uncovering biological pathways that may be targetable by interventions. Growth differentiation factor-15 (GDF-15) plays a significant role in biological aging via multiple biological pathways relevant to age and age-related diseases. Elevated levels of GDF-15 correlate with increasing chronological age, decreased telomerase activity, and increased mortality risk in older adults. We sought to evaluate the circulating levels of GDF-15 in older adults with MDD and its association with depression severity, physical comorbidity burden, age of onset of first depressive episode, and cognitive performance. DesignThis study assayed circulating levels of GDF-15 in 393 older adults (mean ± SD age 70 ± 6.6 years, male:female ratio 1:1.54), 308 with MDD and 85 non-depressed comparison individuals. ResultsAfter adjusting for confounding variables, depressed older adults had significantly higher GDF-15 serum levels (640.1 ± 501.5 ng/mL) than comparison individuals (431.90 ± 223.35 ng/mL) (t=3.75, d.f.= 391, p=0.0002). Among depressed individuals, those with high GDF-15 had higher levels of comorbid physical illness, lower executive cognitive functioning, and higher likelihood of having late-onset depression. ConclusionOur results suggest that depression in late life is associated with GDF-15, a marker of amplified age-related biological changes. GDF-15 is a novel and potentially targetable biological pathway between depression and accelerated aging, including cognitive aging.

Cell non-autonomous effect of hepatic growth differentiation factor 15 on the thyroid gland.

The thyroid gland plays an essential role in the regulation of body energy expenditure to maintain metabolic homeostasis. However, to date, there are no studies investigating the morphological and functional changes of the thyroid gland due to mitochondrial stress in metabolic organs such as the liver. We used data from the Genotype-Tissue Expression portal to investigate RNA expression patterns of the thyroid gland according to the expression of growth differentiation factor 15 (GDF15) such as the muscles and liver. To verify the effect of hepatic GDF15 on the thyroid gland, we compared the morphological findings of the thyroid gland from liver-specific GDF15 transgenic mice to that of wild type mice. High GDF15 expression in the muscles and liver was associated with the upregulation of genes related to hypoxia, inflammation (TGF-α via NFκB), apoptosis, and p53 pathway in thyroid glands. In addition, high hepatic GDF15 was related to epithelial mesenchymal transition and mTORC1 signaling. Electron microscopy for liver-specific GDF15 transgenic mice revealed short mitochondrial cristae length and small mitochondrial area, indicating reduced mitochondrial function. However, serum thyroid stimulating hormone (TSH) level was not significantly different. In our human cohort, those with a high serum GDF15 level showed high fasting glucose, alanine transaminase, and alkaline phosphatase but no difference in TSH, similar to the data from our mice model. Additionally, high serum GDF15 increased the risk of lymph node metastasis to lateral neck. The hepatic GDF15 affected thyroid morphogenesis via a TSH-independent mechanism, affecting aggressive features of thyroid cancers.

Raised circulating soluble growth differentiation factor 15 is negatively associated with testosterone level in hypogonadic men with type 2 diabetes.

Epidemiological studies consistently show that decreases in serum testosterone level are observed more frequently in men with type 2 diabetes mellitus (T2DM), while clinical investigations have demonstrated that an increased level of circulating growth differentiation factor-15 (GDF-15) are also related closely to T2DM. The aim of this study was to examine the potential relationship between serum GDF-15 levels and hypogonadism in Chinese male patients with T2DM. A total of 305 T2DM men were recruited between July 2020 and August 2021. GDF-15 and total testosterone concentrations were quantified by an enzyme-linked immunosorbent assay and LC/MS mass spectrometry, respectively. Multiple linear regression analysis, logistic regression, and restricted cubic splined models were used to examine the correlation between GDF-15 levels and hypogonadism in these patients. When compared with T2DM patients without hypogonadism circulating GDF-15 levels were significantly higher in the hypogonadism group [1081.83 (746.79,1539.94) versus 779.49 (548.46,1001.27), p<0.001] and were associated positively with hypogonadism in unadjusted and fully adjusted multivariate regression models (p<0.01). The fully adjusted regression coefficients with 95% confidence intervals for circulating GDF-15 and testosterone deficiency were -1.795 (-2.929, -0.661). Serum GDF-15 levels were also associated positively with testosterone deficiency in each logistic regression model (p<0.05), while after adjustment for all risk factors, the same findings were obtained in the restricted cubic splined models (p<0.01). In hypogonadal men with T2DM, an elevated serum GDF-15 level is associated negatively with serum testosterone concentration. GDF-15 may be a novel cytokine related to T2DM men with hypogonadism.

GDF-15: A Potential Biomarker and Therapeutic Target in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a rheumatic disease. Growth differentiation factor 15 (GDF-15) is a member of transforming growth factor-β superfamily. To date, association of GDF-15 with SLE pathogenesis is not clarified. This study discussed GDF-15 serum levels and gene polymorphisms in SLE patients and lupus mouse model further demonstrated the role of GDF-15 in lupus development. We conducted two independent case-control studies for SLE patients. One is to evaluate serum levels of GDF-15 in 54 SLE patients and 90 healthy controls, and the other one is to analyze gene polymorphisms of GDF-15 in 289 SLE patients and 525 healthy controls. Serum levels of GDF-15 were detected by ELISA. GDF-15 gene polymorphisms (rs1055150, rs1058587, rs1059519, rs1059369, rs1227731, rs4808793, and rs16982345) were genotyped by the Kompetitive Allele-Specific PCR (KASP) method. Addition of recombinant GDF-15 into pristane-induced lupus mice evaluated histological and serological changes. Results showed that serum levels of GDF-15 were overexpressed in SLE patients and associated with disease activity. Polymorphisms rs1055150, rs1059369, rs1059519, and rs4808793 of GDF-15 gene were related to SLE risk. Lupus mice showed splenomegaly, severe histological scores, and high levels of autoantibodies [antinuclear antibodies (ANA) and total immunoglobulin G (IgG)], whereas administration of GDF-15 into lupus mice reduced the histological changes. Percentages of CD8+, CD11b+, CD19+, CD11C+ cells, TH2 cells, and pro-inflammatory cytokines (IL-1β, IL-2, IL-4, IL-21, and IL-22) were reduced after GDF-15 treatment in lupus mice. In conclusion, GDF-15 was related to lupus pathogenesis and inhibited lupus development.

Growth differentiation factor 15 as a novel diagnostic and therapeutic marker for autoimmune hepatitis

Growth differentiation factor 15 (GDF15) has been reported to be associated with fibrosis and cancer in liver disease. Diagnosis of autoimmune hepatitis (AIH) is often difficult because of the lack of specific markers. We investigated whether GDF15 is useful for diagnosing AIH and determined its therapeutic effects. We enrolled 171 Japanese patients as follows: AIH (n = 45), hepatitis B (HB) (n = 17), hepatitis C (HC) (n = 15), primary biliary cholangitis (PBC) (n = 20), and 74 healthy controls. Serum GDF15 levels were measured, and immunohistological analyses of GDF15 were performed using liver tissue of AIH patients. (1) GDF15 levels (pg/ml) were higher in AIH (1994.3 ± 1258.0) and HC (1568.0 ± 822.3) than in HB (953.2 ± 871.4), PBC (643.9 ± 247.0), and controls (475.3 ± 145.3) (p < 0.0001), as well as in cirrhosis patients (n = 31) than in non-cirrhosis patients (n = 66) (1926.6 ± 1026.0 vs. 1249.1 ± 1124.1, p < 0.0001). In non-cirrhosis patients, GDF15 levels were higher in AIH (1914.0 ± 1327.2) than in HC (955.7 ± 502.7), HB (519.3 ± 197.5), and PBC (643.9 ± 247.0) (p < 0.0001). (2) GDF15 was positively correlated with M2BPGi (r = 0.7728), total bilirubin (r = 0.6231), and PT-INR (r = 0.6332). (3) GDF15 levels could be used to distinguish AIH from other liver diseases in non-cirrhosis patients, with an area under the curve of 0.9373 (sensitivity 93.6%, specificity 79.3%, cut-off value 931.3). (4) GDF15 in AIH decreased after treatment. (5) Immunohistological analyses in AIH liver tissues revealed that GDF15 was strongly expressed in inflammatory cells, hepatic cytoplasm, and sinusoidal endothelial cells, but decreased after treatment. GDF15 is a novel diagnostic marker for AIH and is also expected to be a therapeutic marker for AIH.Clinical Trials Registration: The study protocol was approved by the institutional review board of Kurume University (Approval No.: 19049).

Protective effect of growth differentiation factor 15 in sepsis by regulating macrophage polarization and its mechanism

ABSTRACT This study aims to investigate the protective effect of growth differentiation factor 15 (GDF15) in sepsis by regulating macrophage polarization and its mechanism. The mouse macrophages were cultured and treated with lipopolysaccharide (LPS), and some cells were intervened with GDF15 and LY294002. The proinflammatory activated (M1) macrophages and the anti-inflammatory activated (M2) macrophages were measured and observed, and the messenger RNA expression levels of their biomarkers, phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) were detected. The survival rate, cardiac function, and histopathological sections were observed. In the LPS group, after GDF15 intervention, the percentage of M1 macrophages decreased and M2 macrophages increased, the infiltration of monocytes/macrophages into the heart was inhibited, systemic and cardiac inflammation was reduced, and the survival time of the mice was prolonged. GDF15 regulated macrophage polarization and played an anti-inflammatory role by activating the phosphorylation of the PI3K/Akt signaling pathway. In patients with sepsis, the serum GDF15 level increased and was closely related to the severity of the sepsis and the 28-day mortality rate and could be used as a prognostic marker of sepsis. GDF15 regulates macrophage polarization through activating the PI3K/Akt signaling pathway and has a protective effect on survival and the cardiac function of patients with sepsis and sepsis mouse models. The increase in serum GDF15 level is closely related to severity and mortality in patients with sepsis and is therefore a prognostic marker of sepsis.

Cardioprotective Effect of Growth Differentiation Factor 15 Against Isoproterenol-Induced Cardiomyocyte Apoptosis via Regulation of the Mitochondrial Fusion

Abstract Objective: Pressure overload-induced myocardial apoptosis is a critical pathologically initiated process leading to heart failure (HF). Growth differentiation factor 15 (GDF15) dramatically increases during cardiac hypertrophy and dysfunction, but its functions and mechanisms are barely known. This study aims to elucidate the role and mechanism of GDF15 in HF. Methods: Between January 2017 and August 2018, 57 patients diagnosed with chronic HF (aged &gt;18 years, with left ventricular ejection fraction (LVEF) ≤35%) and 57 non-HF patients (aged &gt;18 years, LVEF &gt;35%) were prospectively enrolled in this study based on the balance of the baseline characteristics. Other acute or chronic diseases and pregnant/lactating women were excluded. The serum concentrations of GDF15 were detected. Isoproterenol (ISO)-induced HF mouse model was established by pumping with ISO (30 mg/(kg·day)) for 4 weeks, and the GDF15 expression in serum and heart tissue was evaluated in vivo. Primary cardiomyocytes were cultured and treated with ISO to induce cardiomyocytes damage. The apoptosis of cardiomyocytes and the effect of GDF15 on ISO-induced cardiomyocytes injury was evaluated in vitro. Results: After adjusting the baseline characteristic, serum levels of GDF15 were significantly higher in HF subjects than in non-HF patients. Similarly, in the ISO-induced HF mouse model, the significant increase in GDF15 was associated with the process of HF in vivo. Moreover, the elevation of GDF15 occurred prior to heart remodeling in the ISO-induced HF mouse model. Furthermore, using primary cardiomyocytes, we demonstrated that the GDF15 was remarkably enhanced in serum from pathological HF patients and cardiac tissue from the ISO-induced mouse model. Reducing GDF15 exaggerated the ISO-induced cell apoptosis by blocking mitochondrial fusion and increasing oxidative stress. In contrast, the silence of GDF15 aggravated the ISO-induced cardiomyocytes damage. Conclusions: GDF15 acts as a protective factor against cardiomyocyte apoptosis by improving mitochondria fusion during HF. These findings indicate that GDF15 may be a potential therapeutic target for HF.

Associations of device-measured sleep, sedentariness and physical activity with growth differentiation factor 15 in older adults.

BackgroundGrowth differentiation factor 15 (GDF‐15) is a biomarker for chronic disease burden that might explain the health effects of sedentary behaviours (SBs) and physical activity (PA). We examined associations of device‐measured sleep, SB and PA, and time reallocations among them, with GDF‐15 in older adults.MethodsWe used data from 2245 older adults participating in the Seniors‐ENRICA‐2 study. Wrist‐worn accelerometers were employed to ascertain total time in sleep, SB, light PA (LPA) and moderate‐to vigorous PA (MVPA). Associations between these activities and serum GDF‐15 levels were analysed using linear regression, including isotemporal substitution models for time reallocations among activities, and adjusted for potential confounders. Analyses were conducted separately in two groups (less active and more active individuals) according to the median total PA time.ResultsIn the less active participants, 30 min/day more of MVPA were related to lower levels of GDF‐15 when replacing sleep (fully adjusted mean percentage differences [95% confidence interval] in GDF‐15 of −9.2% [−13.2, −5.0]), SB (−9.8% [−13.6, −5.8]) and LPA (−5.8% [−11.1, −0.3]), whereas 30 min/day more of LPA were related to lower GDF‐15 when replacing both sleep (−3.6% [−6.1, −1.0]) and SB (−4.2% [−6.7, −1.7]). In the more active participants, 30 min/day more of MVPA were also associated with lower GDF‐15 when replacing sleep (−2.9% [−5.3, −0.3]), SB (−2.4% [−4.6, −0.2]) and LPA (−3.5% [−6.6, −0.3]), but no associations were found for more time in LPA. Spending more time in SB was associated with higher GDF‐15 levels only among those less active (1.9% [0.9, 2.9] per 30 min/day increment). Sleep time did not appear to be associated with GDF‐15.ConclusionsThe MVPA was inversely associated with GDF‐15, with stronger associations at lower PA volumes. Also, more LPA and less SB time were linked to lower GDF‐15 in the less active individuals. This suggests that simply moving more and sitting less may reduce chronic disease burden in older adults.

Elevated Levels of Growth/Differentiation Factor-15 in the Aqueous Humor and Serum of Glaucoma Patients.

Dysregulated levels of growth/differentiation factor-15 (GDF15), a divergent member of the transforming growth factor-beta super family, have been found to be associated with the pathology of various diseases. In this study, we evaluated the levels of GDF15 in aqueous humor (AH) and serum samples derived from primary open-angle glaucoma (POAG) and age- and gender-matched non-glaucoma (cataract) patients to assess the plausible association between GDF15 and POAG. GDF15 levels were determined using an enzyme-linked immunosorbent assay, and data analysis was performed using the Wilcoxon rank sum test, or the Kruskal–Wallis test and linear regression. GDF15 levels in the AH (n = 105) of POAG patients were significantly elevated (by 7.4-fold) compared to cataract patients (n = 117). Serum samples obtained from a subgroup of POAG patients (n = 41) also showed a significant increase in GDF15 levels (by 50%) compared to cataract patients. GDF15 levels were elevated in male, female, African American, and Caucasian POAG patients. This study reveals a significant and marked elevation of GDF15 levels in the AH of POAG patients compared to non-glaucoma cataract control patients. Although serum GDF15 levels were also elevated in POAG patients, the magnitude of difference was much smaller relative to that found in the AH.

Growth Differentiation Factor-15 and Syndecan-1 Are Potential Biomarkers of Cardiac and Renal Involvement in Classical Fabry Disease under Enzyme Replacement Therapy

Background and Aims: Inflammation and endothelial damage play a pivotal role in Fabry disease (FD) manifestations. In daily clinical practice, FD is mainly monitored by traditional biomarkers of target organ injury, such as serum creatinine and proteinuria, which provide no information about inflammation and endothelial damage. Materials and Methods: We investigated the serum levels of 3-nitrotyrosine (3-NT), an oxidative stress biomarker, and of growth differentiation factor-15 (GDF-15) and syndecan-1 in classical FD patients on enzyme replacement therapy (ERT) for at least 6 months and their relationship with Fabry-related cardiac and renal manifestations. Results: Fifty-two classical FD patients (37 females) on ERT for 62.0 ± 27.5 months were included in the study. The main clinical manifestations included nephropathy (67.3%) and cardiomyopathy (21.1%). Serum levels of 3-NT, syndecan-1, and GDF-15 were 33.3 (4.8–111.1) nmol/mL, 55.7 (38.8–74.9) ng/mL, and 541.8 (392.2–784.4) pg/mL, respectively. There was a direct correlation between interventricular septal thickness and serum GDF-15 (r = 0.59; p < 0.001) and syndecan-1 (r = 0.30, p = 0.04). Among kidney parameters, there was a significant correlation between estimated glomerular filtration rate and GDF-15 (r = −0.61; p < 0.001), as well as between 24 h proteinuria and syndecan-1 (r = 0.28; p = 0.04). Serum GDF-15 levels were significantly higher in patients with cardiomyopathy (p = 0.03) as well in those with both nephropathy and cardiomyopathy (p = 0.02) than in patients without these comorbidities. Serum GDF-15 levels were also significantly higher in patients who started ERT at an older age (≥40 years). In multivariate analysis, syndecan-1, 3-NT, GDF-15, time on ERT, and arterial pressure differentiated Fabry patients with both cardiac and renal involvement from those without these manifestations. Conclusions: GDF-15 and syndecan-1 were associated with parameters of cardiac and renal involvement in classic FD patients on ERT. Their potential association with residual risk and disease outcomes should be investigated.

Serum GDF-15 Predicts In-Hospital Mortality and Arrhythmic Risks in Patients With Acute Myocardial Infarction.

This study aims to evaluate the association of serum growth differentiation factor 15 (GDF-15) with in-hospital mortality and arrhythmic risks in patients with acute myocardial infarction (AMI). A total of 296 consecutive patients with AMI were enrolled in our hospital from Jan. 2018 to Dec. 2020. Serum GDF-15 levels were measured at baseline. The primary endpoint was in-hospital all-cause mortality, and the secondary endpoint was major adverse cardiac events (MACEs) during hospitalization, defined as a composite of cardiovascular death, heart failure, sustained ventricular arrhythmias (ventricular tachycardia or ventricular fibrillation), and bleeding. During hospitalization, patients with a higher GDF-15 level had significantly higher incidences of in-hospital mortality (7.4% vs 1.4%; P = .02) and MACEs (9.5% vs 20.9%, P < .01) than those with a lower GDF-15 level. Multivariate logistic regression analysis showed that a higher GDF-15 level was significantly associated with increased risks of in-hospital mortality (OR = 1.92, 95% CI: 1.44-2.50; P < .01) and MACEs (OR = 2.19, 95% CI: 1.56-2.77; P < .01). In conclusion, GDF-15 was associated with the risks of in-hospital mortality and MACEs, indicating that it should be a prognostic biomarker for patients with AMI.

Interactions Between Plasma Amyloid and Aging Markers to Determine Clinically Meaningful Cognitive Decline

Older adults’ experiences with memory problems may be an important indicator of current and future well-being; however, these experiences and their impacts are poorly characterized, particularly in those with co-occurring affective symptoms. The purpose of this mixed-methods study was to examine how the experience of memory problems influences emotional well-being in older adults without dementia, and whether this differs based on cognitive status and current depressive symptoms or anxiety symptoms. A convergent parallel mixed methods design was used in which quantitative and qualitative data were collected simultaneously, analyzed separately, and then integrated to determine how participants’ experiences differed. Community-dwelling older adults (n=49, Mage = 74.5, 63% female) without severe cognitive impairment completed study questionnaires and two individual, semi-structured interviews. Five themes were identified that described the influence of memory problems on emotional well-being: Evoking Emotions, Fearing Future, Undermining Self, Normalizing Problems, and Adjusting Thinking. The extent to which memory problems impacted emotional well-being depended on multiple factors including current affective symptoms (primarily anxiety), characteristics of the experience (such as judgments of its importance), as well as personal experience with dementia. Notably, there were no thematic differences in the emotional impact of memory problems between older adults with normal cognition and those with evidence of mild cognitive impairment. Our findings suggest that thorough assessment of reports of memory problems, regardless of cognitive testing outcomes, should consider co-occurring subsyndromal affective disorders as well as older adults’ evaluations of how memory problems influence their daily lives and well-being.

Interactions Between Plasma Amyloid and Aging Markers to Determine Clinically Meaningful Cognitive Decline

Background: Brain amyloidosis is a well-known pathological hallmark of Alzheimer’s disease (AD) and can be early identified by measuring plasma amyloid-β (Aβ) status. Growing evidence implicates the biological mechanisms of aging, including chronic inflammation, mitochondrial dysfunction and neurodegeneration, in AD pathogenesis. This study aims to investigate the interactions between plasma Aβ status and aging markers on clinically meaningful cognitive decline. Methods: This secondary analysis from Multidomain Alzheimer Preventive Trial (MAPT) enrolled 401 community-dwelling older adults (mean age ± SD: 76.7 ± 4.6 years) who had clinical dementia rating (CDR) scale as 0 or 0.5, and who had their plasma biomarkers measured: amyloidosis: Aβ42/40 ratio; inflammatory: tumor necrosis factor receptor type 1 (TNFR-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP); mitochondrial dysfunction: growth differentiation factor 15 (GDF-15); neurodegeneration: neurofilament light chain (NfL). Cognitive decline was determined by diagnosed dementia and worsening CDR status. Cox regression and moderation modeling were applied to examine the interrelationships between biomarkers and risk of cognitive decline. Results: Among 401 participants, 43.9% were cognitive normal (CDR=0) and 56.1% were mild cognitive impairment (CDR=0.5) initially. After 3.3 ± 1.1 years of follow-up, 7.0% of population evolved dementia and 34.2% had worsening CDR status. GDF-15 and NfL presented prospective associations with incident dementia. However, risk of dementia associated with plasma Aβ did not change after considering the serum level of GDF-15 and NfL. Conclusion: The markers of mitochondrial dysfunction and neurodegeneration did not partially explain the associations between plasma Aβ status and cognitive decline in older adults.

Association of serum growth differentiation factor-15 levels with the risks of death and vascular events in patients with ischemic stroke: The role of diabetes

Background and aimsResearchers have not determined whether the association between growth differentiation factor-15 (GDF-15) levels and stroke outcomes is modified by the diabetes status. We aimed to evaluate the prognostic value of GDF-15 among patients with ischemic stroke stratified by diabetes. Methods and resultsA total of 3001 patients with ischemic stroke were selected from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and included in this study. The primary outcome was a composite outcome of death and vascular events at 3 months after acute ischemic stroke. An elevated GDF-15 level was significantly associated with the primary outcome in patients with diabetes but not in those without diabetes (pinteraction = 0.038). The multivariate-adjusted hazard ratio (95% confidence intervals) for the primary outcome was 3.33 (1.07–10.35) when 2 extreme tertiles were compared, and a linear association between GDF-15 levels and the primary outcome was observed in patients with diabetes (p for linearity = 0.046). The addition of serum GDF-15 to conventional risk factors improved the risk prediction for the primary outcome in patients with diabetes (net reclassification improvement: 31.98%, p = 0.043; integrated discrimination index: 0.85%, p = 0.034) but not in those without diabetes. ConclusionsA modifying effect of the diabetes status on the association between serum GDF-15 levels and ischemic stroke prognosis was observed. Elevated serum GDF-15 levels were associated with the primary outcome within 3 months after ischemic stroke in patients with diabetes, suggesting that GDF-15 may be an important prognostic factor for ischemic stroke in patients with diabetes.

Associations between Sex Hormones and Circulating Growth Differentiation Factor-15 in Male Patients with Major Depressive Disorder

The interaction between the endocrine system and inflammation is crucial pathogenesis of depression. Our study aimed at exploring the possible relationship between sex hormones and growth differentiation factor-15 (GDF-15), a common indicator of inflammation in male patients with major depressive disorder (MDD). Methods: GDF-15 levels of 121 male MDD patients were compared with 105 healthy subjects with the help of a Cobas 8000 automatic chemiluminescence immunoanalyzer. Results: (1) MDD patients showed higher GDF-15 levels, a lower testosterone (T) level and testosterone/estradiol ratio (T/E2 ratio) than healthy subjects (all p < 0.05). (2) Serum T levels and the T/E2 ratio were inversely associated with GDF-15 serum levels (all p < 0.05). (3) HAMD-24 scores were positively correlated with the levels of GDF-15 (p < 0.01), but not with T levels, estradiol (E2) levels, and the T/E2 ratio (all p > 0.05). Conclusion: The high level of GDF-15 was correlated with a low T/E2 ratio and T deficiency in male MDD patients. The above results demonstrate that up-regulation of serum GDF-15 and down-regulation of T and T/E2 ratio may be correlated with the occurrence and severity of depression. So, changing the level of GDF-15 by regulating the proportion of sex hormones may play a key role in the prognosis and treatment of depression.

Serum growth differentiation factor 15 predicts hepatocellular carcinoma occurrence after hepatitis C virus elimination.

After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination. We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct-acting antiviral agents (DAAs). The patients were randomly divided into derivation (n=964) and validation (n=642) cohorts. In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350pg/mL, HR 2.54), AFP (>5ng/mL, HR 2.00), and the FIB-4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB-4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3years was 0.64%, 3.27% and 15.3% in low-score (N=171), medium-score (N=300) and high-score (N=166) groups, respectively. In the total cohort, scoring divided patients with a FIB-4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3years, into medium-score and low-score groups with HCC occurrence rates at 3years of 3.76% and 0.24%, respectively. Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB-4 index can predict de novo HCC occurrence risk after HCV elimination.

Serum levels of the cold stress hormones FGF21 and GDF-15 after cardiac arrest in infants and children enrolled in single center therapeutic hypothermia clinical trials

ObjectiveFibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor-15 (GDF-15) are putative neuroprotective cold stress hormones (CSHs) provoked by cold exposure that may be age-dependent. We sought to characterize serum FGF21 and GDF-15 levels in pediatric cardiac arrest (CA) patients and their association with use of therapeutic hypothermia (TH). MethodsSecondary analysis of serum samples from clinical trials. We measured FGF21 and GDF-15 levels in pediatric patients post-CA and compared levels to both pediatric intensive care (PICU) and healthy controls. Post-CA, we compared normothermia (NT) vs TH (33 °C for 72 h) treated cohorts at < 24 h, 24 h, 48 h, 72 h, and examined the change in CSHs over 72 h. We also assessed association between hospital mortality and initial levels. ResultsWe assessed 144 samples from 68 patients (27 CA [14 TH, 13 NT], 9 PICU and 32 healthy controls). Median initial FGF21 levels were higher post-CA vs. healthy controls (392 vs. 40 pg/mL, respectively, P < 0.001). Median GDF-15 levels were higher post-CA vs. healthy controls (7,089 vs. 396 pg/mL, respectively, P < 0.001). In the CA group, the median change in FGF21 from PICU day 1–3 (after 72 h of temperature control), was higher in TH vs. NT (231 vs. –20 pg/mL, respectively, P < 0.05), with no difference in GDF-15 over time. Serum GDF-15 levels were higher in CA patients that died vs. survived (19,450 vs. 5,337 pg/mL, respectively, P < 0.05), whereas serum FGF21 levels were not associated with mortality. ConclusionSerum levels of FGF21 and GDF-15 increased after pediatric CA, and FGF21 appears to be augmented by TH.