Elevated Growth Differentiation Factor 15 Levels Research Articles

GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway

Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.

The implicated role of GDF15 in gastrointestinal cancer.

Growth differentiation factor 15 (GDF15), a stress-responsive cytokine from transforming growth factor superfamily, is highly expressed in mammalian tissues, including pancreas, stomach and intestine under pathological conditions. In particular, elevated levels of GDF15 might play an important role in the development and progression of various gastrointestinal cancers (GCs), suggesting its potential as a promising target for disease prediction and treatment. In this review, systematic reviews addressing the role of GDF15 in GCs were updated, along with the latest clinical trials focussing on the GDF15-associated digestive malignancies. The multiple cellular pathways through which GDF15 is involved in the regulation of physiological and pathological conditions were first summarized. Then, GDF15 was also established as a valuable clinical index, functioning as a predictive marker in diverse GCs. Notably, latest clinical treatments targeting GDF15 were also highlighted, demonstrating its promising potential in mitigating and curing digestive malignancies. This review unveils the pivotal roles of GDF15 and its potential as a promising target in the pathogenesis of GCs, which may provide insightful directions for future investigations.

Growth Differentiation Factor-15 Is Considered a Predictive Biomarker of Long COVID in Non-hospitalized Patients.

Mitochondrial dysfunction is associated with various diseases. Mitochondria plays a regulatory role during infection. The association between mitokines and subsequent COVID progression has not been previously studied. The retrospective cohort study aimed to investigate the potential of serum mitokines as long COVIDbiomarkers in non-hospitalized patients. Patients with confirmed SARS-CoV-2 infection and blood test reports between January 2021 and April 2023 were included. Patients were categorized into two groups, the recovered and long COVID groups, based on fatigue, decline in focus, and pain. Serum levels of growth differentiation factor 15 (GDF-15) and fibroblast growth factor-21 (FGF-21), which are affected by mitochondrial function, along with inflammatory and vascular endothelium markers, were measured using enzyme-linked immunosorbent assays (ELISA). A receiver operating characteristic curve was used to screen the biomarkers. The threshold value of GDF-15 in the acute phase was 965 pg/mL (sensitivity: 71.4%, specificity: 83.3%), indicating that GDF-15 may be associated with the presence of symptoms three months post onset. No association with inflammatory markers and vascular structures was observed. Therefore, elevated GDF-15 levels in the acute phase may act as a predictive biomarker of long COVID.

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.

High Growth Differentiation Factor-15 (GDF-15) in Rheumatoid Arthritis Patients Potential Risk for Cardiovascular Disease

Rheumatoid arthritis (RA) is a chronic autoimmune disorder primarily affecting joints, leading to pain, stiffness, and functional disability. The inflammatory mechanisms underlying RA also impact various organ systems, with significant implications for morbidity and mortality. In this study, we analyzed the growth differentiation factor-15 (GDF-15), a cytokine implicated in inflammation and associated with RA and cardiovascular diseases. We conducted a case-control study involving 150 RA patients and 150 healthy individuals, assessing various biomarkers (ACPA, CRP, ESR, and RF) including GDF-15, lipid profile, and inflammatory markers. Our results demonstrated significantly elevated levels of GDF-15 in RA patients (309.44 pg/ml) compared to controls (64.40 pg/ml), indicating its potential role as a biomarker for RA and cardiovascular risk (p&lt;0.001). Furthermore, RA patients exhibited dyslipidemia characterized by elevated total cholesterol, triglycerides, LDL cholesterol, and atherogenic indices, along with decreased HDL cholesterol levels, predisposing them to a higher risk of atherosclerosis and cardiovascular complications (p&lt;0.001). Correlation analyses revealed associations between GDF-15 levels, lipid profile parameters, and disease severity markers, highlighting the intricate interplay between inflammation, lipid metabolism, and RA progression. These findings demonstrated the importance of early detection and management of dyslipidemia in RA patients to mitigate cardiovascular risk. Overall, our study contributes to understanding the pathophysiology of RA and identifies potential biomarkers for disease monitoring and risk stratification.

Serum-based biomarkers associated with lung cancer risk and cause-specific mortality in the German randomized Lung Cancer Screening Intervention (LUSI) trial.

Lung cancer (LC) screening can be optimized using individuals' estimated risks of having a detectable lung tumor, as well as of mortality risk by competing causes, to guide decisions on screening eligibility, ideal screening intervals and stopping ages. Besides age, sex and smoking history, blood-based biomarkers may be used to improve the assessment of LC risk and risk of mortality by competing causes. In the German randomized Lung Screening Intervention Trial (LUSI), we measured growth/differentiation factor-15 (GDF-15), interleukin-6 (IL-6), C-reactive protein (CRP) and N-terminal pro-brain natriuretic protein (NT-proBNP), in blood serum samples collected at start of the trial. Participants in the computed tomography (CT)-screening arm also had a pulmonary function test. Regression models were used to examine these markers as predictors for impaired lung function, LC risk and mortality due to LC or other causes, independently of age, sex and smoking history. Our models showed increases in LC risk among participants with elevated serum levels of GDF-15 [odds ratio (OR)Q4-Q1 =2.47, 95% confidence interval (CI): 1.49-4.26], IL-6 [ORQ4-Q1 =2.36 (1.43-4.00)] and CRP [ORQ4-Q1 =1.81 (1.08-2.75)]. Likewise, proportional hazards models showed increased risks for LC-related mortality, hazard ratio (HR)Q4-Q1 of 4.63 (95% CI: 2.13-10.07) for GDF-15, 3.56 (1.72-7.37) for IL-6 and 2.34 (1.24-4.39) for CRP. All four markers were associated with increased risk of mortality by causes other than LC, with strongest associations for GDF-15 [HRQ4-Q1 =3.04 (2.09-4.43)] and IL-6 [HRQ4-Q1 =2.98 (2.08-4.28)]. Significant associations were also observed between IL-6, CRP, GDF-15 and impaired pulmonary function [chronic obstructive pulmonary disease (COPD), preserved ratio impaired spirometry (PRISm)]. Multi-marker models identified GDF-15 and IL-6 as joint risk predictors for risk of LC diagnosis, without further discrimination by CRP or NT-proBNP. A model based on age, sex, smoking-related variables, GFD-15 and IL-6 provided moderately strong discrimination for prediction of LC diagnoses within 9 years after blood sampling [area under the curve (AUC) =74.3% (57.3-90.2%)], compared to 67.0% (49.3-84.8%) for a model without biomarkers. For mortality by competing causes, a model including biomarkers resulted in an AUC of 76.2% (66.6-85.3%)], compared to 70.0% (60.9-77.9%) a model including age, sex and smoking variables. Serum GDF-15 and IL-6 may be useful indicators for estimating risks for LC and competing mortality among long-term smokers participating in LC screening, to optimize LC screening strategies.

Creation of a Peptide Antagonist of the GFRAL-RET Receptor Complex for the Treatment of GDF15-Induced Malaise.

Growth differentiation factor 15 (GDF15) is a contributor to nausea, emesis, and anorexia following chemotherapy via binding to the GFRAL-RET receptor complex expressed in hindbrain neurons. Therefore, GDF15-mediated GFRAL-RET signaling is a promising target for improving treatment outcomes for chemotherapy patients. We developed peptide-based antagonists of GFRAL that block GDF15-mediated RET recruitment. Our initial library screen led to five novel peptides. Surface plasmon resonance and flow cytometric analyses of the most efficacious of this group, termed GRASP, revealed its capacity to bind to GFRAL. In vivo studies in rats revealed that GRASP could attenuate GDF15-induced nausea and anorexia resulting from cisplatin. Combined with Ondansetron, GRASP led to an even greater attenuation of the anorectic effects of cisplatin compared to either agent alone. Our results highlight the beneficial effects of GRASP as an agent to combat chemotherapy-induced malaise. GRASP may also be effective in other conditions associated with elevated levels of GDF15.

Shexiang Baoxin Pill treats acute myocardial infarction by promoting angiogenesis via GDF15-TRPV4 signaling

Angiogenesis has been considered a pivotal strategy for treating ischemic heart disease. One possible approach, the Shexiang Baoxin Pill (MUSKARDIA), has been noted to promote angiogenesis, but its underlying mechanism is still largely unknown. We aimed to determine the effects of MUSKARDIA on acute myocardial infarction (AMI), as well as the underlying mechanistic bases. AMI was induced in rats, using left anterior descending coronary arterial occlusion, and either 6 (low) or 12 (high-dose) mg/kg/day of MUSKARDIA was administered for 56 days. We found that MUSKARDIA improved cardiac function and counteracted against adverse remodeling among AMI rats, which most likely is due to it promoting angiogenesis. Transcriptome analysis by RNA-sequencing found that MUSKARDIA up-regulated cardiac pro-angiogenic genes, particularly growth differentiation factor 15 (GDF15), which was confirmed by RT-qPCR. This up-regulation was also correlated with elevated serum GDF15 levels. In vitro analyses with human umbilical vein endothelial cells found that increased GDF15, stimulated by MUSKARDIA, resulted in enhanced cell migration, proliferation, and tubular formation, all of which were reversed after GDF15 knockdown using a lentiviral vector. Gene Ontology, as well as Kyoto Genes and Genomes enrichment analyses identified calcium signaling pathway as a major contributor to these outcomes, which was verified by Western blot and Cal-590 AM loading showing that transient receptor potential cation channel subfamily V member 4 protein (TRPV4) and intracellular Ca2+ levels increased in accordance with MUSKARDIA-induced GDF15 up-regulation, and decreased with GDF15 knock-down. Therefore, MUSKARDIA may exert its cardioprotective effects via stimulating the GDF15/TRPV4/calcium signaling/angiogenesis axis.

Growth differentiation factor‑15 in patients with gestational diabetes mellitus and its relationship with microalbuminuria.

Gestational diabetes mellitus (GDM) is a common pregnancy-related complication and growth differentiation factor-15 (GDF-15) is involved in a number of diseases; therefore, the aim of the present study was to investigate the level and clinical significance of serum GDF-15 levels in patients with GDM. A total of 237 pregnant women at 20-24 weeks of gestation were selected and assigned to a normal pregnancy group (70 patients) and a GDM group (167 patients) according to the presence or absence of GDM. The general clinical data of the two groups were collected. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, glycated hemoglobin, fasting insulin, 24-h urinary albumin and serum GDF-15 levels were measured. The results showed that the body mass index (BMI) of the GDM group was higher than that of the normal pregnancy group. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, fasting insulin, glycated hemoglobin and GDF-15 levels and the positive rate of microalbuminuria were significantly higher in the GDM group compared with the normal pregnancy group. GDF-15 levels were positively correlated with BMI, fasting plasma glucose, glycated hemoglobin, homeostasis model assessment-insulin resistance and fasting insulin levels. Logistic regression analysis suggested that elevated GDF-15 levels are an independent risk factor for microalbuminuria. In conclusion, serum GDF-15 levels are strongly associated with GDM and elevated GDF-15 levels are an independent risk factor for microalbuminuria. Serum GDF-15 may act as a novel biomarker for predicting microalbuminuria in GDM patients.

Screening study of anti-emetics to improve GDF15-induced malaise and anorexia: Implications for emesis control

Considerable preclinical and clinical attention has focused on the food intake and body weight suppressive effects of growth differentiation factor 15 (GDF15) and its elevated blood levels as a consequence of disease states and disease treatment therapeutics. We have previously reported that exogenous administration of GDF15 induces anorexia through nausea and emesis in multiple species. Importantly, GDF15 signaling as a meditator of chemotherapy-induced anorexia and emesis has recently been demonstrated in both murine and nonhuman primate models. The mechanism, however, by which GDF15 induces malaise and the utility of existing therapeutic targets to counteract its effects remain largely unknown. Using a dose of GDF15 that mimics stimulated levels following chemotherapy administration and reliably induces malaise, we sought to screen anti-emetics that represent distinct pharmacotherapeutic classes hypothesized to reduce GDF15-induced effects in rats. Strikingly, our results showed that none of the tested compounds were effective at preventing GDF15-induced malaise. These results illustrate the complexity of GDF15 signaling mechanism and may have important implications for medical conditions characterized by elevated GDF15 levels and incomplete symptom control, such as chemotherapy-induced nausea and vomiting.

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.

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.

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.

154-OR: The Site Specific Role of GDF15 in Metformin Action

Metformin lowers glucose levels, appetite and body weight in rodents and humans, but the mechanisms on energy balance regulation have been rarely studied. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels in humans and rodents, while elevating GDF15 via GDF15 infusion in rodents lowers food intake and body weight via its receptor GDNF family receptor α-like (GFRAL) , which is expressed in the hindbrain nucleus area postrema (AP) . However, whether the GDF15-GFRAL axis in the AP mediates metformin effect is unknown. In this study, metformin (200 mg/kg) was infused into the upper small intestine (USI) of rats, while fasting-refeeding study or intravenous glucose tolerance test was performed. USI metformin infusion elevated plasma GDF15 levels (met 138 ± 25 vs. veh 59 ± 7 pg/ml, n = 8, p &amp;lt; 0.01) in parallel to a lowering of food intake (met 30 ± 2 vs. veh 40 ± 2 kcal, n = 16, p &amp;lt; 0.01) and an increase in glucose tolerance (AUC met 5243 ± 75 vs. veh 5674 ± 153, n = 7, p &amp;lt; 0.05) . Further, metformin lowered not only food intake but also body weight gain by 12 h (met 14 ± 1 vs. veh 23 ± 3 g, n = 8, p &amp;lt; 0.01) . Importantly, a knockdown of GFRAL achieved via an injection of lentivirus expressing shRNA GFRAL vs. mismatch into the AP by ∼40% (p &amp;lt; 0.05) negated the ability of metformin to not only lower food intake and body weight, but also increase glucose tolerance independent of body weight. Finally, acute AP GDF15 infusion (2 pmol) decreased food intake (GDF15-25 ± 2 vs. veh-36 ± 3 kcal, n = 10, p &amp;lt; 0.01) and weight gain (as early at 6 h, GDF15 3.6 ± 1.2 vs. vehicle 8.7 ± 1.6 g, n = 10, p &amp;lt; 0.05) , and increased glucose tolerance independently from body weight (AUC, GDF15-5322 ± 94 vs. veh-5722 ± 169, n = 6, p &amp;lt; 0.05) , and these metabolic effects of AP GDF15 infusion were prevented by GFRAL knockdown in the AP. In summary, our findings indicate that the AP GDF15-GFRAL axis is sufficient and necessary for metformin to regulate energy and glucose homeostasis in rodents. Disclosure S.Zhang: None. R.Li: None. Z.Danaei: None. Y.Lim: None. T.K.Lam: None. Funding Canadian Institutes of Health Research (FDN-143204)

Risk stratification using growth differentiation factor 15 in patients undergoing transcatheter aortic valve implantation.

Growth differentiation factor 15 (GDF15) shows potential predictive value in various cardiac conditions. We investigated relationships between GDF15 and clinical or procedural outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) in order to propose clinically useful predictive risk stratification model. This prospective single-center registry enrolled 88 consecutive patients with severe symptomatic aortic stenosis treated with TAVI. Clinical parameters were collected and biomarkers including GDF-15 were measured within 24 h before TAVI. All relevant clinical outcomes according to the Valve Academic Research Consortium-2 were collected over the follow-up period. The cohort included 52.3% of females. The mean age of study participants was 81 years; the mean Society of Thoracic Surgeons (STS) score and logistic EuroSCORE were 3.6% and 15.4%, respectively. The mortality over the entire follow-up period was 10.2%; no death was observed within the first 30 days following TAVI. Univariate analysis showed significant associations between GDF15 and mortality (P=0.0006), bleeding (P=0.0416) and acute kidney injury (P=0.0399). A standard multivariate logistic regression model showed GDF-15 as the only significant predictor of mortality (P=0.003); the odds ratio corresponding to an increase in GDF15 of 1000 pg/mL was 1.22. However, incremental predictive value was not observed when the STS score was combined with GDF15 in this predictive model. Based on our observations, preprocedural elevated GDF15 levels are associated with increased mortality and demonstrate their additional value in predicting adverse clinical outcomes in a TAVI population.

Protein Biomarkers Predict Risk of Gastrointestinal Bleeding in Left Ventricular Assist Device Patients

<h3>Purpose</h3> Recently, protein biomarkers such as N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) have been shown to predict risk for gastrointestinal bleeding (GIB) and stroke in atrial fibrillation. This study aims to assess the validity of these biomarkers in predicting the incidence of stroke or GIB in LVAD recipients. <h3>Methods</h3> Prospective LVAD patients were enrolled into the PREVENtion of Heartmate II Pump Thrombosis through Clinical Management (PREVENT) at 24 sites across the U.S along with patients from Inova Heart and Vascular Institute and Allegheny Health Network from 2014-2019. NT-proBNP and GDF-15 were measured before LVAD. Time to first stroke or GIB within 6-months was analyzed in relationship to the median biomarker concentration. <h3>Results</h3> A total of 470 patients were included in the analysis. Patients had the following characteristics: median patient age 60 years (IQR: 52-67), 80% male, 20% female, 75% White, 20% Black, 30% diabetes mellitus and 34% atrial fibrillation. Most patients had non-ischemic cardiomyopathy (46%) and were INTERMACS profile 2-3 (67%). At 6-months, 99 patients had a GIB (21%) and 32 had a stroke (7%). The median NT-proBNP was 2,551pg/ml (1,396-5,386) and GDF-15 was 5,000pg/ml (2,917-8,442). When patients were separated by the median biomarker concentrations, no difference in the incidence of stroke was noted (<i>p</i>=0.8). Similarly, the incidence of GIB with higher NT-proBNP concentrations was not significant (<i>p</i>=0.16, Figure A). Higher GDF-15 concentrations were associated with a higher incidence of GIB (<i>p</i>=0.02, Figure B). Patients with elevated GDF-15 levels had an incidence of GIB of 23% compared to 15% in patients with lower concentrations. <h3>Conclusion</h3> Elevated levels of GDF-15 predict risk of GIB following LVAD implant. These data highlight the ability of novel biomarkers to predict complications that could potentially guide the selection of antithrombotic therapy after LVAD placement.

Growth differentiation factor-15 as an emerging biomarker for identifying myositis

ABSTRACT Introduction The autoimmune disorders of the skeletal muscle tissue termed myositis are a rare yet diverse group of diseases with distinct clinical and pathological features and with different prognoses and treatment responses. Subtyping of patients is necessary for appropriate disease management, and requires specialized expertise and elaborate diagnostic testing of clinico-pathological disease features. Areas covered Current clinical practice and diagnostic criteria for subtyping patients are searched on medical online platforms including PubMed and Web of Science. Recent publications on growth differentiation factor-15 (GDF-15) and muscle disorders are summarized and analyzed, and comparisons are made of data published in studies describing disease cohorts as well as individual patients. Influence of age and physical activity on GFD-15 levels and potential as a diagnostic criterion are discussed. This review contains supportive evidence of the elevated levels of GDF-15 in the blood of myositis patients, a feature which distinguishes these autoimmune muscle disorders from muscular dystrophy with secondary inflammation. Expert opinion GDF-15 represents a novel and promising serological biomarker for diagnosing myositis, yet more studies are needed to assay its sensitivity and specificity. Increased diagnostic power is expected by combining GDF-15 levels with other blood-derived biomarkers.

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.

Investigating the Correlation between Growth Differentiation Factor 15 Serum Level and Its Gene Expression with Psoriasis and Its Severity.

Psoriasis is a chronic inflammatory dermatitis characterized by an inflammatory epidermal hyperproliferation. Growth differentiation factor-15 (GDF-15), a member of the transforming growth factor-β family, has immune modulatory roles in autoimmune condition of Psoriasis. This study aimed to evaluate the relationship between GDF-15 serum levels as well as gene expression with psoriasis and its severity. This case-control study was performed on 45 patients with psoriasis Vulgaris and 45 healthy individuals. The severity of the disease was determined based on the psoriasis area and severity index (PASI score). Serum levels of GDF-15 were measured by enzyme-linked immunosorbent assay (ELISA) and its gene expression in peripheral blood mononuclear cells was quantified by real-time polymerase chain reaction (RT-PCR). The mean serum levels of GDF-15 in patients and controls were 1.98±1.57 ng/mL and 0.93±0.48 ng/mL, respectively. GDF-15 gene expression was measured as 9.7±6.6% in the patient group and 7.6±2.5% in the healthy group. The mean of GDF-15 serum levels in mild, moderate, and severe cases of psoriasis were 0.45±0.35, 2.27±0.7, and 3.5±1.6 ng/mL, respectively, indicating that elevated serum levels of GDF-15 correlate significantly with disease severity. The mean of GDF-15 gene expression in the mild, moderate, and severe forms of psoriasis were 5.25±3.2, 7.6±2.8, and 17.8±5.7, respectively which indicate a significant relationship between GDF-15 gene expression and psoriasis severity. Based on this study, in psoriatic patients, GDF-15 serum levels and gene expression are significantly higher than those in healthy controls. Such values were correlated with disease activity, especially in severe cases. Therefore, GDF-15 may be used as a prognostic marker of psoriasis.

Changes in systemic GDF15 across the adult lifespan and their impact on maximal muscle power: the Copenhagen Sarcopenia Study

BackgroundAlthough growth differentiation factor 15 (GDF15) is known to increase with disease and is associated with low physical performance, the role of GDF15 in normal ageing is still not fully understood. Specifically, the influence of circulating GDF15 on impairments in maximal muscle power (a major contributor to functional limitations) and the underlying components has not been investigated.MethodsData from 1305 healthy women and men aged 20 to 93 years from The Copenhagen Sarcopenia Study were analysed. Circulating levels of GDF15 and markers of inflammation (tumor necrosis factor‐alpha, interleukin‐6, and high‐sensitivity C‐reactive protein) were measured by ELISA (R&D Systems) and multiplex bead‐based immunoassays (Bio‐Rad). Relative (normalized to body mass), allometric (normalized to height squared), and specific (normalized to leg muscle mass) muscle power were assessed by the Nottingham power rig [leg extension power (LEP)] and the 30 s sit‐to‐stand (STS) muscle power test. Total body fat, visceral fat, and leg lean mass were assessed by dual energy X‐ray absorptiometry. Leg skeletal muscle index was measured as leg lean mass normalized to body height squared.ResultsSystemic levels of GDF15 increased progressively as a function of age in women (1.1 ± 0.4 pg·mL−1·year−1) and men (3.3 ± 0.6 pg·mL−1·year−1) (both P < 0.05). Notably, GDF15 increased at a faster rate from the age of 65 years in women (11.5 ± 1.2 pg·mL−1·year−1, P < 0.05) and 70 years in men (19.3 ± 2.3 pg·mL−1·year−1, P < 0.05), resulting in higher GDF15 levels in men compared with women above the age of 65 years (P < 0.05). Independently of age and circulatory markers of inflammation, GDF15 was negatively correlated to relative STS power (P < 0.05) but not LEP, in both women and men. These findings were mainly explained by negative associations of GDF15 with specific STS power in women and men (both P < 0.05).ConclusionsA J‐shaped relationship between age and systemic GDF15 was observed, with men at older age showing steeper increases and elevated GDF15 levels compared with women. Importantly, circulating GDF15 was independently and negatively associated with relative STS power, supporting the potential role of GDF15 as a sensitive biomarker of frailty in older people.