Elevated GDF15 Research Articles

ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal cancer.

Reversing cancer cachexia remains a challenge. Genetic biomarkers for the early detection of the disease have been explored in order to enable the implementation of preventive measures. We therefore genotyped candidate genes based on cachexia phenotype and quantified adiponectin and GDF-15 levels in cachectic patients with gastrointestinal cancer. Patients with a diagnosis of gastrointestinal cancer were divided into a cachectic and a non-cachectic group after the start of chemotherapy. A control group (no cancer) was also included. We genotyped the following single nucleotide polymorphisms (SNPs) by quantitative PCR: FOXO3 (rs1935949), FOXO3 (rs4946935), ACVR2B (rs2268757), and SELP (rs6136). In addition, we quantified adiponectin and GDF-15 levels by ELISA. The rs2268757 SNP in the ACVR2B gene was associated with the weight loss phenotype in cachectic patients with gastrointestinal cancer (non-cachectic, P = 0.004). Plasma adiponectin levels were higher in cachectic patients compared to controls (P = 0.01) and non-cachectic patients (P = 0.004). GDF-15 was also elevated in cachectic patients compared to controls (P < 0.0001) and non-cachectic patients (P = 0.001). Analysis by sex showed elevated adiponectin levels in men (control, P = 0.01) and cachectic women (control, P = 0.04; non-cachectic, P = 0.01), as well as elevated GDF-15 levels in men (control, P = 0.002) and cachectic women (control, P = 0.002; non-cachectic, P = 0.007). However, there was no significant difference in the levels of these cytokines between cachectic men and women. The results suggest the rs2268757 SNP in the ACVR2B gene, adiponectin, and GDF-15 as potential biomarkers of cachexia in gastrointestinal cancer.

Elevated GDF-15 is associated with stroke severity, myocardial injury and poor clinical outcome in patients after acute ischemic stroke

Abstract Background GDF-15 is emerging as a biomarker of cardiometabolic risk and disease burden. Increased concentrations of circulating GDF-15 are associated with increased mortality in patients with acute coronary syndromes or heart failure. Purpose We aimed to describe relation between GDF-15 elevation with stroke severity, myocardial injury and poor clinical outcome in patients after acute ischemic stroke (AIS). Methods Patients after AIS were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24 and 48 hours later to determine the plasma levels of GDF-15 and high-sensitive troponin I (hs-cTnI). Receiver-operating characteristic (ROC) curve analysis was used to determine the diagnostic accuracy and optimal elevation cut-off values of GDF-15 on day 1 for the severity of acute stroke defined by NIHSS score. The optimal cut off in our group was 1776 pg/ml (Sensitivity 0,8, Specificity 0,52). Myocardial injury was defined by fourth universal definition of myocardial infarction using hs-cTnI. Demographic characteristics, clinical data, functional outcome, and all-cause mortality at 1 year were compared between groups according to GDF-15 levels. National Institutes of Health Stroke Scale (NIHSS) at the time of admission and the modified Rankin Scale (mRS) 90 days following the patient’s discharge from the hospital were used to assess stroke severity and clinical outcome. All analyses were performed with SPSS 29.0 (SPSS Inc). Results Between August 2020 and August 2022, 177 patients after AIS were enrolled. Elevated GDF-15 was observed in 71 patients (40,1%). Most common comorbidities included arterial hypertension, dyslipidemia, type 2 DM and atrial fibrillation. In analysis, we observed a connection between elevated GDF-15 with unfavourable outcome evaluated by mRS at 90 days (HR 2.57, 95% CI 1,44 to 4,57, p=0.001) and with all-cause death at 1 year (HR 4.479, 95% CI 1,81 to 11,09, p=0.001). GDF-15 elevation was associated with myocardial injury (Figure 1C). Moreover, individuals with moderate to severe and severe strokes (NIHSS 16-42) displayed higher GDF-15 levels compared to those with minor to moderate stroke (Figure 1D). The Kaplan-Meier survival curve accentuated a significantly elevated all-cause mortality among patients with increased GDF-15 (p &amp;lt; 0.001) (Figure 2). In multivariate regression analysis elevated GDF-15 was associated with atrial fibrillation and high-sensitive troponin I elevation. Conclusion The conclusions drawn suggest that heightened GDF-15 is associated with increased stroke severity, myocardial injury and unfavourable outcome.

The role of GDF15 in attenuating noise-induced hidden hearing loss by alleviating oxidative stress

Noise-induced hidden hearing loss (HHL) is a newly uncovered form of hearing impairment that causes hidden damage to the cochlea. Patients with HHL do not have significant abnormalities in their hearing thresholds, but they experience impaired speech recognition in noisy environments. However, the mechanisms underlying HHL remain unclear. In this study, we developed single-cell transcriptome profiles of the cochlea of mice with HHL, detailing changes in individual cell types. Our study revealed a transient threshold shift, reduced auditory brainstem response wave I amplitude, and decreased number of ribbon synapses in HHL mice. Our findings suggest elevated oxidative stress and GDF15 expression in cochlear hair cells of HHL mice. Notably, the upregulation of GDF15 attenuated oxidative stress and auditory impairment in the cochlea of HHL mice. This suggests that a therapeutic strategy targeting GDF15 may be efficacious against HHL.Graphical HHL mice had a transient threshold shift, reduced ABR wave I amplitude, and decreased number of ribbon synapses.HHL mice's cochlear hair cells exhibited increased oxidative stress and elevated GDF15 expression.Upregulation of GDF15 attenuated oxidative stress and auditory damage in the cochlea of HHL mice, implying that GDF15-targeted treatment techniques may be useful for HHL.

Elevated cerebrospinal fluid neuronal injury biomarkers within 24 hours of onset in infection-triggered acute encephalopathy compared to complex febrile seizures

ObjectiveThis study aimed to measure and compare cerebrospinal fluid neuronal injury biomarkers in the acute phase of complex febrile seizure (CFS) and infection-triggered acute encephalopathy (AE). Furthermore, we determined the pathogenesis of AE with biphasic seizures and late reduced diffusion (AESD). MethodsPediatric patients with febrile status epilepticus who visited Hyogo Prefectural Kobe Children's Hospital from November 1, 2016, to December 31, 2022, and whose cerebrospinal fluid samples were collected within 24 h of neurological symptom onset were included. Patients were classified as having CFS or infection-triggered AE according to their definitions. Patients with AE were further categorized into AESD or unclassified AE. Cerebrospinal fluid biomarkers (neuron-specific enolase, growth differentiation factor 15 [GDF-15], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein, and tau protein were measured and compared among the groups. ResultsTotal of 63 patients (45 with CFS and 18 with AE) were included. Among the AE patients, nine were classified as having AESD and nine as having unclassified AE. S100B levels were significantly higher in patients with AESD than in patients with CFS (485 pg/ml vs. 175.3 pg/ml) and were even higher in patients with AESD and neurological sequelae (702.4 pg/ml). GDF-15 levels were significantly elevated in patients with AE compared to patients with CFS (85.8 pg/ml vs. 23.6 pg/ml). ConclusionsThe elevation of S100B suggests that activated astrocytes may be closely associated with the early pathology of AESD. Elevated GDF-15 levels in infection-triggered AE suggest the activation of defense mechanisms caused by stronger neurological injury.

Abstract 3072: GDF15 Represses The Interferon Response Early In Vascular Senescence

Senescent cells have been identified as major contributors of the progression of vascular diseases including atherosclerosis by increasing the senescence-associated secretory phenotype (SASP) and dysregulating vascular cells. Notably, senescence and the SASP can contribute to plaque rupture and atherosclerotic progression by promoting inflammation and plaque vulnerability. A time course microarray analysis of vascular smooth muscle cell (VSMC) senescence revealed p53-regulated GDF15 mRNA was increased early and remained elevated throughout senescence. Notably, GDF15 has been implicated as a biomarker for cardiovascular disease mortality and is part of the conserved SASP across cell types and tissues. Interestingly, intracellular or secreted GDF15 protein levels were increased in monkeys fed a high-fat diet or in mice fed a high-fat diet and in individuals with high Framingham risk scores, respectively. We sought to identify the role of GDF15 in senescent VSMCs. Using CRISPRi, we silenced GDF15 during early senescence and performed RNA-sequencing. Pathway analysis revealed a enrichment in interferon signaling with the loss of GDF15. Coinciding with the increase in interferon signaling, phosphorylation of STAT1 and CREB were increased by loss of GDF15 in early senescence, aiding in the elevation of interferon expression. Given the role of interferons in communication and the prominence of macrophages in atherosclerosis, we tested the effects of conditioned media, derived from either proliferating or senescent VSMCs, on the activation and the expression of scavenger receptors on human macrophages. Senescent conditioned media increased expression of ABCG1 , CD36 , LOX-1 , SCARF1 , and GDF15 mRNA as well as TNFα and CCL2 secretion in macrophages. We propose that elevated GDF15 levels in early senescence suppress interferon signaling, thus preventing macrophage chemotaxis and in turn leading to the accumulation of senescent cells in the vasculature. Thus, disrupting the senescent VSMC-macrophage communication through secreted proteins may offer promising avenues of therapeutic development to prevent or improve inflammatory vascular diseases.

Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study.

Atrial fibrillation (AF) and concomitant cardiometabolic disease processes interact and combine to lead to adverse events, such as stroke, heart failure, myocardial infarction, and cardiovascular death. Circulating biomolecules provide quantifiable proxies for cardiometabolic disease processes. The aim of this study was to test whether biomolecule combinations can define phenotypes in patients with AF. This pre-specified analysis of the EAST-AFNET 4 biomolecule study assigned patients to clusters using polytomous variable latent-class analysis based on baseline concentrations of 13 precisely quantified biomolecules potentially reflecting ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome, the primary outcome of EAST-AFNET 4, were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow-up 2.9 years).Unsupervised biomolecule analysis assigned 1586 patients (71 years old, 46% women) into four clusters. The highest risk cluster was dominated by elevated bone morphogenetic protein 10, insulin-like growth factor-binding protein 7, N-terminal pro-B-type natriuretic peptide, angiopoietin 2, and growth differentiation factor 15. Patients in the lowest risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of C-reactive protein, interleukin-6, and D-dimer. Patients in the highest risk cluster had a five-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control was effective across clusters (Pinteraction = 0.63). Sensitivity analyses and external validation in BBC-AF replicated clusters and risk gradients. Biomolecule concentrations identify cardiometabolic subphenotypes in patients with AF at high and low cardiovascular risk.

GDF15 as a potential biomarker to distinguish fibrotic from non-fibrotic hypersensitivity pneumonitis

Hypersensitivity Pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) characterized by fibrotic HP (fHP) or non-fibrotic HP (non-fHP). Fibrosis is associated with poor prognosis, emphasizing the need for biomarkers to distinguish fHP from non-fHP. This study aimed to determine the plasma levels of GDF15 in HP patients and assess its association with lung function and phenotype classification. GDF15 levels were quantified by ELISA in HP (n = 64), idiopathic pulmonary fibrosis (n = 54), and healthy control (n = 128) groups. Clinical, demographic, and functional data were obtained from medical records. High-resolution chest CT scans were used to classify HP patients into fHP and non-fHP groups. In addition, receiver operating characteristic analysis was performed to determine the cut-off point, sensitivity, and specificity. Our results revealed significantly elevated GDF15 levels in fHP compared to non-fHP (2539 ± 821 pg/ml versus 1783 ± 801 pg/ml; p = 0.009). The estimated cut-off point for plasma GDF15 levels to distinguish fHP from non-fHP was 2193.4 pg/ml (AUC 0.75). These findings suggest that GDF15 may serve as a valuable biomarker for differentiating between fHP and non-fHP, potentially indicating its involvement in lung fibrosis development in HP.

GDF-15 alleviates diabetic nephropathy via inhibiting NEDD4L-mediated IKK/NF-κB signalling pathways

Podocyte inflammatory injury has been indicated to play a pivotal role in the occurrence and development of diabetic nephropathy (DN). However, the pathogenesis of inflammation remains unclear. Recent researches have shown that GDF-15, a member of the transforming growth factor-β superfamily, were elevated under pathological conditions, such as myocardial ischemia, cancer, as well as inflammation. Here, we demonstrated that GDF-15 could alleviate podocyte inflammatory injury by modulating the NF-κB pathway. GDF-15 and other pro-inflammatory factors, such as TNF-α, IL-1β, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF-15 was also elevated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes. The silence of GDF-15 in HG-stimulated podocytes further augmented inflammation and podocyte injury, while overexpression of GDF-15 significantly reduced the inflammatory response in podocytes. Mechanistically, we demonstrated that GDF-15 could inhibit the nuclear translocation of NF-κB through IKK and IκBα by interaction with ubiquitin ligase NEDD4L. Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.

Abstract LB_C02: A phase 1b dose escalation study of AV-380 in combination with standard of care chemotherapy in metastatic cancer patients (pts) with cachexia and elevated GDF-15 levels

Abstract Background: Cancer cachexia is a complex metabolic syndrome characterized by involuntary weight loss, muscle wasting and weakness leading to resistance to therapy and high mortality. Elevated levels of circulating GDF-15, an inflammatory cytokine involved in stress response and body weight regulation, are common in cancer pts with cachexia. Furthermore, GDF-15 expression increases in proportion to disease severity, and preclinical models have shown that elevated levels of circulating GDF-15 elicit cachexia. AV-380 is an antibody that binds with high affinity to GDF-15 resulting in its elimination from circulation. It has been shown to reverse weight loss and increase recovery of muscle in animal cancer models and was well tolerated without serious AEs in a phase 1 study in healthy subjects. The current study is designed to determine if adding AV-380 to standard-of-care (SoC) chemotherapy will confer additional clinically meaningful benefits in metastatic cancer pts with cachexia. Methods: This is an open-label, dose escalation, multicenter phase 1b study to assess the safety, PK, and PD of AV-380. Eligible pts must be ≥18 years of age, have confirmed metastatic colorectal or pancreatic cancer, actively receiving 1st-line SoC chemotherapy (&amp;gt;2 cycles of FOLFOX/FOLFOXIRI±bevacizumab for colorectal, FOLFOX/FOLFIRINOX for pancreatic), have cachexia defined by Fearon criteria (weight loss &amp;gt;5% over past 6 months w/o simple starvation, or BMI &amp;lt;20 kg/m2 or sarcopenia plus any degree of weight loss &amp;gt;2%), life expectancy ≥3 months, GDF-15 &amp;gt;1200 pg/mL, and ECOG PS 0/1. Those with brain metastases (unless treated and stable for ≥2 weeks prior to study treatment), significant cardiovascular disease, corrected QT interval &amp;gt;460 ms, uncontrolled pleural or pericardial effusion, parenteral nutrition, or non-cancer related cachexia are excluded. Primary endpoints are AE characterization, serum PK parameters, and serum levels of GDF-15; secondary endpoints include assessments of weight/BMI, cachexia measures, and anti-AV-380 antibodies; and exploratory endpoints include best objective response and biomarkers. Five escalating dose cohorts of AV-380 are planned (50, 100, 200, 400, 800 mg IV) with 4-6 pts in each and following a standard 3+3 design. Dose de-escalation will be performed if the lowest dose cohort is successful. The study is structured into 28-day courses with Course 1 being the single-dose phase of AV-380 and Course 2 starting the multiple-dose phase where AV-380 is administered every 14 days. Pts will remain enrolled until they start 2nd-line systemic anticancer therapy, have unacceptable toxicity related to AV-380, complete 4 courses of AV-380, withdraw consent, or sponsor terminates study. Statistical analyses will be done by cohort and summarized descriptively. Clinicaltrials.gov: NCT05865535 Encore abstract. Originially accepted at the annual Cancer Cachexia Society meeting, 28-30 September 2023, Edinburgh Scotland. Citation Format: Arvind Chaudhry, RIchard Zuniga, J. Eva Selfridge, Bruno Bastos, Vipin Lohiya, Martin Birkhofer. A phase 1b dose escalation study of AV-380 in combination with standard of care chemotherapy in metastatic cancer patients (pts) with cachexia and elevated GDF-15 levels [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C02.

SAT674 Lipodystrophy: A Hidden Culprit In Uncontrolled Diabetes

Abstract Disclosure: F. El Sayed: None. A. Banka: None. Introduction: Lipodystrophies are rare disorders with selective absence/accumulation of fat tissue. The “common” genetic forms include Congenital Generalized Lipodystrophy or Familial Partial Lipodystrophy (FPLD). Non-genetic factors like autoimmune disorders, chronic infections, or malnutrition can also contribute to a lipodystrophy phenotype. Clinical case: A 49-year-old female with diabetes mellitus, hypertriglyceridemia, gait disturbances, hypertension, hereditary hemorrhagic telangiectasias, asthma, presents with suspected lipodystrophy. She notes truncal obesity as a child, with progression as an adult and subsequent loss of volume from her arms and legs around age 30. Family history is significant for multiple family members with diabetes mellitus. On physical exam, the patient has a BMI of 22.86 kg/m2. She walks with a cane and has abdominal fat deposition, a dorsocervical fat pad, and reduced fat and muscle mass in her lower extremities. Her diabetes is poorly controlled with multiple complications including retinopathy, microalbuminuria, neuropathy, CVA, and CAD. Her medications include metformin, pioglitazone, detemir, aspart, and an insulin sliding scale for diabetes management, and rosuvastatin, fenofibrate, and omega-3-acid ethyl esters for hyperlipidemia. Her last A1C was 12.7%, and urine analysis was positive for glucosuria and ketonuria. Her lipid panel revealed high triglycerides (800s) and low HDL levels. Other pertinent labs include elevated GDF15 at 761 pg/mL. and lactate elevation at 3.4 mml/L. Given suspicion for hypercortisolism, she underwent a dexamethasone suppression test which was negative for Cushing’s disease. She subsequently underwent exome sequencing with mitochondrial deletion testing, which led to the diagnosis of FPLD. Discussion: FPLD results in loss of fat from the extremities starting around puberty, often leading to metabolic complications. Although both sexes are affected, women usually present with more severe disease. Currently, multiple genes are associated with FPLD, most commonly LMNA and PPARG which both follow autosomal dominant inheritance. Conclusion: Presently, there is no cure for lipodystrophy syndromes. However, in patients with diabetes and resistant metabolic syndrome features, a diagnosis of lipodystrophy should be considered. Further evaluation with genetic testing is warranted and has implications for family planning and medical management. Presentation: Saturday, June 17, 2023

Mitochondrial metabolism related markers GDF-15, FGF-21, and HIF-1α are elevated in pediatric migraine attacks.

The purpose of this study was to investigate the serum levels of mitochondrial metabolism/reactive oxygen species (ROS)-related peptides (hypoxia inducible factor-1α [HIF-1α], fibroblast growth factor-21 [FGF-21], growth differentiation factor-15 [GDF-15]) and key migraine-related neuropeptides (calcitonin gene-related peptide [CGRP], pituitary adenylate cyclase-activating peptide-38 [PACAP-38], substance P [SP], and vasoactive intestinal peptide [VIP]) during migraine attacks and to evaluate their diagnostic value in pediatric migraine. There is increasing evidence for the important role of impairment in oxidative mitochondrial metabolism in the pathophysiology of migraine. Potential biomarkers that may reflect the relationship between migraine and mitochondrial dysfunction are unclear. A total of 68 female pediatric migraine patients without aura and 20 female healthy controls aged 8-18 years, admitted to the hospital, were enrolled in this cross-sectional study. Serum concentrations of these molecules were determined by enzyme-linked immunosorbent assays, and clinical features and their possible diagnostic value were analyzed. Serum levels of HIF-1α (252.4 ± 51.9 [mean ± standard deviation]) pg/mL), GDF-15 (233.7 ± 24.7 pg/mL), FGF-21 (96.1 ± 13.1 pg/mL), CGRP (44.5 ± 11.3), and PACAP-38 (504.7 ± 128.9) were significantly higher in migraine patients compared to healthy controls (199.8 ± 26.8, 192.8 ± 20.7, 79.3 ± 4.1, 34.1 ± 3.5 and 361.2 ± 86.3 pg/mL, respectively). The serum levels of these peptides were also higher in patients with chronic migraine than in patients with episodic migraine, and higher in the ictal period than in the interictal period. A positive correlation was found between attack frequency and both HIF-1α and FGF-21 levels in migraine patients. Serum levels of VIP and SP were not different between the migraine patients and healthy controls. Migraine attacks are accompanied by elevated HIF-1α, FGF-21, GDF-15, CGRP, and PACAP-38 in medication-naive pediatric patients with migraine. Elevated circulating mitochondrial metabolism/ROS-related peptides suggest a mitochondrial stress in pediatric migraine attacks and may have potential diagnostic value in monitoring disease progression and treatment response in children. Novel approaches intervening with mitochondrial metabolism need to be investigated.

Correlation between serum GDF-15 level and pulmonary vascular morphological changes and prognosis in patients with pulmonary arterial hypertension.

To investigate how serum GDF-15 concentration affects pulmonary artery hemodynamics and pulmonary vascular morphological changes in patients with pulmonary arterial hypertension. A total of 45 patients admitted to our hospital from December 2017 to December 2019, were selected for the study. Pulmonary vascular hemodynamics and pulmonary vascular morphology were detected by RHC and IVUS. Serum GDF-15 levels were detected by enzyme-linked immunosorbent assay (ELISA). Based on the concentration of GDF-15, the patients were divided into two groups-the normal GDF-15 group (GDF-15 <1,200 pg/ml, 12 cases) and the elevated GDF-15 group (GDF-15 ≥1,200 pg/ml, 33 cases). A statistical analysis was performed to compare the effects of normal blood GDF-15 levels and high serum GDF-15 levels on hemodynamics and pulmonary vascular morphology in each group of patients. The average levels of RVP, sPAP, dPAP, mPAP, and PVR in patients with elevated GDF-15 levels were higher than those in patients with normal GDF-15 levels. The difference between the two groups was statistically significant (P < 0.05). The average levels of Vd, elastic modulus, stiffness index β, lesion length, and PAV in the normal GDF-15 group were lower than those in the elevated GDF-15 group. The average levels of compliance, distensibility, and minimum l umen area were higher than those in the elevated GDF-15 group. The difference between the two groups was statistically significant (P < 0.05). The survival analysis results showed that the 1-year survival rate of patients with normal GDF-15 levels and elevated GDF-15 levels was 100% and 87.9%, respectively, and that the 3-year survival rate of patients with normal GDF-15 levels and elevated GDF-15 levels was 91.7% and 78.8%, respectively. The survival rates of the two groups were compared by the Kaplan Meier method, and the difference was not statistically significant (P > 0.05). Patients with pulmonary arterial hypertension with elevated GDF-15 levels have higher pulmonary arterial pressure, higher pulmonary vascular resistance, and more serious pulmonary vascular lesions, which are potentially more harmful. There was no statistically significant difference in survival rates among patients with different serum GDF-15 levels.

Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation.

Cardiac functional and structural remodeling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations. ENGAGE AF-TIMI 48 was a randomized trial of edoxaban vs warfarin in 21,105 patients with AF. We performed a nested biomarker study in 8,765 patients, analyzing high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) at baseline and 12 months. Of 8765 patients, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly-reduced EF (HFmrEF; 40-49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT-proBNP, and GDF-15 were associated with higher risk of hospitalization for HF (HHF)/HF death overall and in subpopulations defined by HF history and EF (P<0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (P-interaction>0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF/HF death in overall population (P<0.001 for each biomarker and category). Serial measurement of hsTnT, NT-proBNP, and GDF-15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF.

Distinct single-cell immune ecosystems distinguish true and de novo HBV-related hepatocellular carcinoma recurrences

ObjectiveRevealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies.DesignWe performed 5’and VDJ single-cell RNA-sequencing on 34 samples from...

GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans.

Growth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known. Plasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16). The splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P<0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P<0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue. In humans, GDF15 is a "hepatokine" which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans.

Growth differentiation factor 15 at 3 months after an acute chest pain admission is associated with increased risk of death and cardiovascular events

Abstract Background Growth differentiation factor 15 (GDF-15) is related to increased risk of death and cardiovascular events when measured at initial presentation in patients with acute chest pain. Whether follow-up measurements at 3 months provide prognostic information is unknown. Purpose This study sought to investigate the ability of GDF-15 to predict long-term prognosis when measured 3 months after an acute chest pain admission. Methods GDF-15 was measured at baseline and 3 months after admission in 760 patients admitted with suspected NSTEMI-ACS. NSTEMI-ACS was diagnosed in 228 (30%) patients. Patients were followed for a median of 1480 (17–2118) days. GDF-15 concentration on admission and at 3-months was skewed and therefore compared using the related samples Wilcoxon signed ranked test. A baseline GDF-15 concentration of 1200pg/ml (previously defined as the 90th percentile in a healthy population) was used to divide patients into high and low concentration groups. Kaplan-Meier plots were generated and adjusted hazard ratios were estimated using multiple Cox proportional hazard regression analysis (adjusting for age, sex, hypercholesterolemia, current smoking, diabetes, hypertension, previous myocardial infarction, eGFR &amp;lt;60 ml/min/1.73 m2 and cardiac troponin T). The primary endpoint was all-cause mortality following the 3-month visit and a secondary endpoint included all-cause mortality, future AMI and heart failure hospitalization. Results Median GDF-15 concentration on admission was 940 pg/ml (IQR: 678–1464) and similar to the concentration at 3 months: 927 pg/ml (IQR: 652–1431), p=0.183. In the high-concentration group (n=249) 45 (18%) patients died, and 62 (25%) met the secondary endpoint. In the low-concentration group (n=511) 9 (1.7%) patients died (negative predictive value: 98.2%) and 22 (4%) met the secondary endpoint (negative predictive value: 95.6%). Patients with persistently elevated GDF-15 at the 3 months follow-up visit carried the highest risk for death and cardiovascular events, followed by patients who developed high concentrations during the 3-month follow-up period. Patients with elevated levels at baseline who return to normal concentrations had similar risk as patients with low levels in both measurements (Figure 1). The Kaplan-Meier curves demonstrated an increased risk of the primary and secondary endpoint in the high concentration group (Figure 2). GDF-15 concentration &amp;gt;1200 pg/ml at 3 months was an independent predictor of all-cause mortality with an adjusted HR for death of 4.0 (1.7–9.5, p=0.001) and for the secondary endpoint (adjusted HR 2.9, 95% CI: 1.6–5.4, p=0.001). Conclusion Elevated GDF-15 three months after admission due to suspected NSTEMI-ACS independently predicts long-term mortality and cardiovascular events, irrespective of GDF-15 values during admission. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Western Norway Regional Health Authority

A Wars2 mutant mouse shows a sex and diet specific change in fat distribution, reduced food intake and depot-specific upregulation of WAT browning.

Background: Increased waist-to-hip ratio (WHR) is associated with increased mortality and risk of type 2 diabetes and cardiovascular disease. The TBX15-WARS2 locus has consistently been associated with increased WHR. Previous study of the hypomorphic Wars2 V117L/V117L mouse model found phenotypes including severely reduced fat mass, and white adipose tissue (WAT) browning, suggesting Wars2 could be a potential modulator of fat distribution and WAT browning. Methods: To test for differences in browning induction across different adipose depots of Wars2 V117L/V117L mice, we measured multiple browning markers of a 4-month old chow-fed cohort in subcutaneous and visceral WAT and brown adipose tissue (BAT). To explain previously observed fat mass loss, we also tested for the upregulation of plasma mitokines FGF21 and GDF15 and for differences in food intake in the same cohort. Finally, to test for diet-associated differences in fat distribution, we placed Wars2 V117L/V117L mice on low-fat or high-fat diet (LFD, HFD) and assessed their body composition by Echo-MRI and compared terminal adipose depot weights at 6 months of age. Results: The chow-fed Wars2 V117L/V117L mice showed more changes in WAT browning marker gene expression in the subcutaneous inguinal WAT depot (iWAT) than in the visceral gonadal WAT depot (gWAT). These mice also demonstrated reduced food intake and elevated plasma FGF21 and GDF15, and mRNA from heart and BAT. When exposed to HFD, the Wars2 V117L/V117L mice showed resistance to diet-induced obesity and a male and HFD-specific reduction of gWAT: iWAT ratio. Conclusion: Severe reduction of Wars2 gene function causes a systemic phenotype which leads to upregulation of FGF21 and GDF15, resulting in reduced food intake and depot-specific changes in browning and fat mass.

Abstract 5301: GDF-15 neutralizing antibody restores cancer-induced cachexia

Abstract Growth and differentiation factor 15 (GDF-15) is a member of the transforming growth factor β superfamily. Elevated GDF-15 level was often the result of pathological conditions, including autoimmune disease and cancer. Increased GDF-15 caused metabiotic disorders such as anorexia and cachexia, and GDF-15 became an attractive target for metabolic intervention. Here, we developed a humanized GDF-15 neutralizing antibody (H53E5-8V2) from hybridoma of mice immunized with GDF-15-mFc. H53E5-8V2 had high affinity to GDF-15 (Kd=0.05nM), and demonstrated a stronger binding to coated GDF-15-HIS than Ponsegnomab (Pfizer Inc.) with ELISA assay (EC50=0.33nM vs 0.73nM). H53E5-8V2 also had strong binding to cynoGDF15 (EC50=0.3nM). In ELISA blocking assay, H53E5-8V2 disrupted the interaction of GDF-15 and GFRAL with a lower concentration than Ponsegnomab (EC50=0.25nM vs. 0.5nM). In addition, H53E5-8V2 neutralized GDF-15 in the culture medium and blocked GDF-15 induced GFRAL signaling more efficiently than Ponsegnomab in reporter cell assay (EC50=0.13nM vs. 0.27nM). H53E5-8V2 was stable and had a serum half-life of 9 days in mice with a single antibody injection. And it prevented body weight decrease of the mouse with HT1080 xenograft tumor, MC38 overexpressing GDF-15, or subcutaneous injection of protein GDF-15 fused with mouse Fc at C terminal. These results suggested that H53E5-8V2 was a good candidate drug for the treatment of cachexia. Citation Format: Guojin Wu, Jinming Liang, Feng He, Meng Zhang, Zhengcheng Guo, Jinying Ning. GDF-15 neutralizing antibody restores cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5301.

Heightened levels of plasma growth differentiation factor 15 in men living with HIV.

Plasma biomarkers that reflect energy balance disorders in people living with HIV (PLWH) remain limited. Growth differentiation factor 15 (GDF15) abundance in plasma of mice and humans induces negative energy balance but also becomes highly elevated in obesity and other metabolic diseases. We sought to compare plasma GDF15 levels in PLWH and HIV‐negative persons and mouse models expressing the HIV accessory protein Vpr (that recapitulate HIV‐associated metabolic disorders) and determine their relationship to metabolic parameters. We measured liver Gdf15 mRNA levels and plasma GDF15 levels in male Vpr mice and littermate controls. In parallel, we analyzed plasma GDF15 levels in 18 male PLWH on stable, long‐term antiretroviral therapy and 13 HIV‐negative men (6 healthy controls and 7 with metabolic syndrome). Plasma GDF15 levels were correlated with anthropometric and immune cell parameters in humans. Gene expression analysis of Vpr mouse liver demonstrated elevated Gdf15 mRNA. Plasma GDF15 levels were also higher in Vpr mouse models. Levels of plasma GDF15 in PLWH were greater than in both HIV‐negative groups and correlated positively with the CD4/CD8 T cell ratio in PLWH. Plasma GDF15 levels correlated positively with age in the HIV‐negative subjects but not in PLWH. Since GDF15 levels predict fatty liver disease and energy balance disorders, further studies are warranted to determine the effect of GDF15 in mediating the metabolic disturbances that occur in Vpr mice and PLWH.

Camptothecin effectively treats obesity in mice through GDF15 induction.

Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15’s anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15’s specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.