Plasma Growth Differentiation Factor-15 Research Articles

Urine Growth Differentiation Factor-15 is Not an Independent Biomarker of Cardio-Renal Interactions in Patients with Heart Failure

Introduction Growth differentiation factor-15 (GDF-15) is a stress-responsive biomarker that is elevated in patients with heart failure (HF) and carries prognostic value. However, conditions other than HF can increase levels, making plasma concentration non-specific for HF. In diabetic patients, urinary GDF-15 has been associated with worse kidney function, but its role in HF remains unknown. Therefore, we sought to determine if urinary GDF-15 might provide unique cardio-renal information in patients with HF. Hypothesis Urinary GDF-15 will be associated with diuretic efficiency and survival, independently of plasma GDF-15. Methods GDF-15 was measured in 171 patients with heart failure treated with IV diuretics in the outpatient setting. Pre and post diuretic spot urinary GDF-15 (n=166) was measured using the Mesoscale Assay platform (MesoScale Diagnostics, Gaithersburg, MD, USA). Urinary GDF-15 was normalized to urine creatinine. Diuretic efficiency was defined as sodium excretion per doubling of loop diuretic dose. Results Plasma GDF-15 was weakly correlated with pre-diuretic urinary GDF-15 (r= 0.21, p=0.019) and modestly correlated with post-diuretic urinary GDF-15 (r=0.50, p Conclusion Plasma, but not urinary, GDF-15 was independently associated with diuretic efficiency and survival. This suggests that urinary GDF-15 does not provide specific cardio-renal information, likely because it is mainly filtrated from plasma rather than produced in the kidney.

Abstract 2622: Plasma growth diefferentiation factor-15 is and independen marker for aggressive disease in endometrial cancer

Abstract Objective: Better biomarkers are needed in order to identify patients with endometrial carcinoma at risk of recurrence and who may profit from a more aggressive treatment regimen. Our objective was to explore the applicability of plasma growth differentiation factor 15 (GDF-15) as a marker for recurrent disease, as well as a marker for poor prognosis and lymph node metastases. Methods: EDTA-blood samples were obtained from 235 patients with endometrial cancer before primary surgery. For 36 of these patients, matching blood samples were collected at time of recurrence. Blood samples were also collected from 78 patients with endometrial hyperplasia. Plasma GDF-15 was measured by an enzyme-linked immunosorbent assay (ELISA). Preoperative pelvic MRI scans for 141 patients were investigated in parallel for imaging variables. Results: Preoperative plasma level of GDF-15 was significantly higher for patients who experienced recurrence (1780 ng/L; 95% CI; 518-9475 ng/L) than for patients who did not develop recurrent disease (1236 ng/L; 95% CI; 307-7030 ng/L) (p<0.001). Plasma levels of GDF-15 at recurrence (2818 ng/L, 95% CI 2088-3548 ng/L) were significantly higher than plasma levels of GDF-15 measured at time of primary diagnosis (1857 ng/L, 95% CI; 1317-2398 ng/L) (p=0.001). High plasma level GDF-15 independently predicts recurrent disease (OR=3.14; 95% CI 2.10-4.76) and lymph node metastases (OR=2.64; 95% CI 1.52-4.61). Patients with high plasma level of GDF-15 had significantly larger tumor volume (p=0.008). Conclusion: Elevated plasma level of GDF-15 is associated with aggressive disease and lymph node metastasis in endometrial carcinoma. GDF-15 may be helpful in indicating recurrent disease. Citation Format: Hilde Engerud. Plasma growth diefferentiation factor-15 is and independen marker for aggressive disease in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2622.

Growth Differentiation Factor-15 (GDF-15) Is Associated With Mortality in Ischemic Stroke Patients Treated With Acute Revascularization Therapy.

Background and Aims: Growth differentiation factor-15 (GDF-15) has been identified as a robust marker of developing cardiovascular disease, however, little is currently known about its prognostic value in stroke patients. In a context of growing interest to discover new biomarkers in stroke, we aimed to assess the association between circulating GDF-15 levels and three-month mortality in ischemic stroke patients treated with acute revascularization therapy.Methods: 173 patients hospitalized for acute ischemic stroke and treated with either intravenous thrombolysis (n = 99, 57.2%), mechanical thrombectomy (n = 41, 23.4%) or combined therapy (n = 33, 19.1%) were prospectively included. Baseline clinical and biological characteristics were recorded. Plasma GDF-15 levels were measured at admission (D0), and at 24 h, 3 and 7 days. Clinical severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) score, and vital status was obtained 3 months after the stroke.Results: At 3 months post-stroke, 32 patients (18.5%) had died. The deceased patients had higher D0 plasma GDF-15 levels (median [IQR]: 2,777 [1,769–5,446] vs. 1,460 [965–2,079] pg/mL, P < 0.001). In multivariable logistic regression analysis, D0 GDF-15 levels in the third tertile of the distribution were independently associated with mortality at 3 months (OR = 3.71; 95% CI: 1.09–12.6, P = 0.036), even after adjustment for confounding variables including clinical severity.Conclusions: Our data show for the first time that GDF-15 plasma concentration at admission is independently associated with 3-month mortality in ischemic stroke patients treated with acute revascularization therapy. The pathophysiological mechanisms that could explain this association warrant further study.

Ischemic stroke alters myocardial function and cardioprotective pathways: Potential involvement of GDF15

Both clinical and experimental data suggest that ischemic stroke deleteriously impacts heart functioning. We aimed to evaluate how prior cerebrovascular lesions may affect myocardial contractility and to assess the potential involvement of growth differentiation factor 15 (GDF15), an emerging biomarker in cardiovascular diseases, in this brain-heart interactions. Adult male Wistar rats underwent cerebral embolization by microspheres injection. In vivo, using echocardiography, left ventricular (LV) fractional shortening was altered in both stroke groups 2H (37.9 ± 0.6 [left], 36.9 ± 0.9 [right] vs. 41.4 ± 0.7 [sham]), 24H (39.1 ± 0.4 [left], 36.7 ± 0.6 [right] vs. 43.4 ± 0.7 [sham]) and 7 days after surgery (38.3 ± 0.7 [left], 36.0 ± 0.7 [right] vs. 41.7 ± 0.6 [sham]). In another set of experiments, each heart was isolated and perfused ex vivo in the Langendorff mode. Two hours and 24 hours after stroke, the baseline LV developed pressure in hearts from both stroke groups was diminished. GDF15 plasma levels were increased 2H and 24H after surgery in rats from both stroke groups compared with the sham group. GDF15 gene expression was induced 2H after cerebral embolization in the ipsilateral cortex (10.0 ± 4.5 [left], 10.0 ± 5.0 [right] vs. 1.0 ± 0.1 [sham]) but not in other peripheral tissues such as the heart or liver. Additionally, a decreased protein expression of Survivor Activating Factor Enhancement (SAFE) cardioprotective pathway was observed in the hearts of stroke rats. The lack of decrease at the gene expression level suggests post-translational stroke-induced down-regulations of SAFE pathway in the heart. This study highlighted the deleterious consequences of stroke on cardiac function at different times after stroke both ex vivo and in vivo. The molecular mechanisms involved in these processes need to be further investigated insofar as they may involve cytokines such as GDF15 that may have impaired cardioprotective pathways.

Exercise training promotes a GDF15-associated reduction in fat mass in older adults with obesity.

Obesity is a major risk factor for metabolic disease. Growth differentiation factor 15 (GDF15) has shown promise as a weight loss agent for obesity in animal studies. In healthy lean humans, fasting plasma GDF15 increases after acute exercise. However, the role of GDF15 in human obesity and the response of plasma GDF15 to exercise training in patients with obesity is unknown. Here, 24 sedentary volunteers with obesity [age: 65 ± 1 yr; body mass index (BMI): 35.3 ± 0.9 kg/m2] participated in a supervised 12-wk aerobic exercise intervention: 1 h/day, 5 days/wk at ~85% maximum heart rate with controlled isocaloric diet. As a result, plasma GDF15 was significantly increased (PRE: 644.1 ± 42.6 pg/ml, POST: 704.4 ± 47.2 pg/ml, P < 0.01) after the exercise intervention. Inconsistent with animal models, ΔGDF15 was not correlated with change in weight, BMI, or resting energy expenditure. However, ΔGDF15 was correlated with a reduction in total fat mass (P < 0.05), abdominal fat mass (P < 0.05), and android fat mass (P ≤ 0.05). Participants with a positive GDF15 response to exercise had increased total fat oxidation (PRE: 0.25 ± 0.05 mg·kg-1·min-1, POST: 0.43 ± 0.07 mg·kg-1·min-1, P ≤ 0.05), metabolic flexibility [PRE: -0.01 ± 0.01 delta respiratory quotient (RQ), POST: 0.06 ± 0.01 delta RQ, P < 0.001], and insulin sensitivity (PRE: 0.33 ± 0.01 QUICKI index, POST: 0.34 ± 0.01 QUICKI index, P < 0.01), suggesting a link between GDF15 and fat mass loss as well as exercise-induced metabolic improvement in humans with obesity. We conclude that the exercise-induced increase in plasma GDF15 and the association with reduced fat mass may indicate a role for GDF15 as a therapeutic target for human obesity.

Effect of bariatric surgery on plasma GDF15 in humans.

Bariatric surgery results in marked body weight loss and improves type 2 diabetes in most patients with obesity. The growth differentiation factor 15 (GDF15) has recently emerged as a novel satiety factor. To begin to understand whether GDF15 is involved in mediating the effects of bariatric surgery on body weight and glycemia in humans, we measured plasma GDF15 in patients with obesity ( n = 25) and in patients with obesity and diabetes ( n = 22) before and after Roux-en-Y gastric bypass (RYGB) surgery. GDF15 was increased 1 wk after RYGB compared with before surgery (689 ± 45 vs. 487 ± 28 pg/ml, P < 0.001) and GDF15 remained elevated at 3 mo (554 ± 37 pg/ml, P < 0.05), at 1 yr (566 ± 37 pg/ml, P < 0.05), and at 2.5-4 yr (630 ± 50 pg/ml, P < 0.001) after RYGB surgery. Both age and insulin sensitivity correlated with GDF15 before the surgery ( r = 0.46, P < 0.0001 and r = 0.34, P < 0.001, respectively). These correlations disappeared at 2.5-4 yr following the surgery. Conversely, weight loss magnitude correlated with GDF15, measured 2.5-4 yr postsurgery ( r = 0.21, P < 0.0055). In summary, circulating GDF15 increases and correlates with body weight loss following RYGB surgery.

Plasma growth differentiation factor-15 is an independent marker for aggressive disease in endometrial cancer.

ObjectiveBetter biomarkers are needed in order to identify patients with endometrial carcinoma at risk of recurrence and who may profit from a more aggressive treatment regimen. Our objective was to explore the applicability of plasma growth differentiation factor 15 (GDF-15) as a marker for recurrent disease, as well as a marker for poor prognosis and lymph node metastases.MethodsEDTA-blood samples were obtained from 235 patients with endometrial cancer before primary surgery. For 36 of these patients, matching blood samples were collected at time of recurrence. Blood samples were also collected from 78 patients with endometrial hyperplasia. Plasma GDF-15 was measured by an enzyme-linked immunosorbent assay (ELISA). Preoperative pelvic MRI scans for 141 patients were investigated in parallel for imaging variables.ResultsPreoperative plasma level of GDF-15 was significantly higher for patients who experienced recurrence (1780 ng/L; 95% CI; 518–9475 ng/L) than for patients who did not develop recurrent disease (1236 ng/L; 95% CI; 307–7030 ng/L) (p<0.001). Plasma levels of GDF-15 at recurrence (2818 ng/L, 95% CI 2088–3548 ng/L) were significantly higher than plasma levels of GDF-15 measured at time of primary diagnosis (1857 ng/L, 95% CI; 1317–2398 ng/L) (p = 0.001). High plasma level GDF-15 independently predicts recurrent disease (OR = 3.14; 95% CI 2.10–4.76) and lymph node metastases (OR = 2.64; 95% CI 1.52–4.61). Patients with high plasma level of GDF-15 had significantly larger tumor volume (p = 0.008).ConclusionElevated plasma level of GDF-15 is associated with aggressive disease and lymph node metastasis in endometrial carcinoma. GDF-15 may be helpful in indicating recurrent disease.

Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension

IntroductionSkeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other...

A1630 Association between growth differentiation factor 15 and left ventricular hypertrophy in hypertensive patients and healthy adults

Objectives: Growth differentiation factor 15 (GDF-15) as an independent biomarker of cardiovascular diseases merits further evaluation. Methods: We studied the association between plasma GDF-15 levels and left ventricular hypertrophy (LVH) in hypertensive patients and healthy adults. Hypertensive LVH measurements were performed via echocardiography and analyzed using the cube formula, and human GDF-15 together with interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) concentrations were determined via enzyme-linked immunosorbent assay (ELISA). Results: A total of 302 participants were recruited for this clinical study. Circulating GDF-15, IL-6 and MMP-9 levels were significantly higher in LVH patients (n = 67) than in non-LVH patients (n = 172) and healthy controls (n = 63) (p < 0.001). After adjustment for confounders via multivariate logistic regression, elevated plasma GDF-15 concentrations remained independently associated with LVH in hypertensive patients. In addition, GDF-15 was positively correlated with IL-6 and MMP-9 levels in human plasma, respectively, suggesting that a link exists between GDF-15 expression and inflammation. We also calculated an optimal GDF-15 cut-off point with which LVH severity can be predicted in the current study. Conclusion: GDF-15 is associated with hypertensive LVH and may be a powerful biomarker with which LVH risk can be predicted in patients with hypertension.

Abstract 371: Cardiac Endocrinology: Biology of a Heart-derived Hormone That Regulates Body Growth

The endocrine system is crucial for maintaining whole-body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than ANP and BNP discovered over 30 years ago. We recently identified growth differentiation factor 15 (GDF15) as a heart-derived hormone that regulates body growth. Pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. Blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a bona fide heart-derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive. In addition, we used massively parallel single-nucleus RNA-Seq to decipher cardiac cell type specific gene regulatory network that induces GDF15 transcription in heart disease condition. We further determined how GDF15 precursor is processed into mature hormone. Together these studies reveal a new endocrine mechanism (cardiac endocrinology) by which the heart coordinates cardiac function and body growth.

Additional Diagnostic Value of Growth Differentiation Factor-15 (GDF-15) to N-Terminal B-Type Natriuretic Peptide (NT-proBNP) in Patients with Different Stages of Heart Failure.

BackgroundGrowth differentiation factor-15 (GDF-15) is a promising biomarker of cardiac remodeling. The purpose of this study was to explore the diagnostic value of plasma GDF-15 levels in different stages of heart failure (HF) and to assess the relationship with ventricular remodeling.Material/MethodsWe enrolled 219 HF patients from the Department of Cardiology in Tianjin Union Medical Center as the HF group and 32 healthy subjects as the control group. Circulating GDF-15, NT-proBNP, procollagen I C-terminal propeptide (PICP), and N-terminal procollagen III propeptide (PIIINP) levels were measured using ELISA. Associations between GDF-15 and clinical indicators in cardiac remodeling were assessed using receiver operating characteristic (ROC) curves and Spearman correlation. All the patients were followed up for 1 year.ResultsThe level of plasma GDF-15 in HF patients was higher than in the control group (P<0.05) and increased with higher ACCF/AHA and NYHA classification (P<0.05). Patients with HFrEF had higher GDF-15 levels compared to patients with HFmrEF (P<0.05). GDF-15 and left ventricular mass index (LVMI) were significantly increased as early as the pre-clinical HF stage. Also, GDF-15 levels were positively correlated to LVMI (r=0.433, P<0.05), PICP (r=0.378, P<0.001) and PIIINP (r=0.382, P<0.001). ROC curves were constructed and GDF-15 plus NT-proBNP (AUC=0.905, 95%CI: 0.868–0.942, P<0.001) was superior to NT-proBNP (AUC=0.869, 95%CI: 0.825–0.913, P<0.001) in identifying HF. GDF-15 levels did not predict prognosis after a 1-year follow-up period.ConclusionsGDF-15 combined with NT-proBNP significantly improves the accuracy of diagnosing HF. Plasma GDF-15 levels can indirectly reflect the degree of cardiac remodeling and fibrosis.

Human Aging and Longevity Are Characterized by High Levels of Mitokines.

Mitochondrial stress elicits the production of stress response molecules indicated as mitokines, including fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), and humanin (HN). Many diseases are characterized by progressive mitochondrial dysfunction with alterations of mitokine secretion. It is still controversial whether healthy aging and extreme longevity are accompanied by an altered production of mitokines. We analyzed FGF21, HN, and GDF15 plasma levels in 693 subjects aged from 21 to 113 years, and the association of these mitokines with parameters of health status. FGF21, HN, and GDF15 resulted increased in old age, with the highest levels found in centenarians. These molecules are associated with worsened parameters (such as handgrip strength, insulin sensitivity, triglycerides), particularly in 70-year-old persons, and their levels are inversely correlated with survival in the oldest subjects. Considering the positive biological effect of these molecules, our results can be interpreted in the framework of the hormetic paradigm as an attempt of the cells/tissues to cope with a stress that can have beneficial or detrimental effects depending on its intensity. Finally, persons with Down Syndrome (characterized by accelerated aging) have higher levels of GDF15 and HN with respect to their siblings, suggesting that these molecules, especially GDF15, could be considered markers of biological age.

GDF15 Is a Contraction-Induced Myokine That Regulates Pancreatic ß-Cell Function

β-cell dysfunction plays a major role in the onset of type 2 diabetes (T2D). Exercise improves or restores β-cell function in both humans and rodents with T2D. The specific mechanism is unclear. We hypothesized that exercise-induced myokines engage in cross-talk with the pancreas to help regulate β-cell function and mass. To test our hypothesis, differentiated C2C12 myotubes were subjected to electrical pulse stimulation (EPS) to simulate in vivo exercise. EPS-conditioned media from the contracting myotubes significantly elevated glucose-stimulated insulin secretion (GSIS) in β-cells vs. non-EPS control conditions (P&amp;lt;0.05). RNA-sequencing and bioinformatic analysis enabled us to identify Growth Differentiation Factor 15 (GDF15) as a novel contraction-induced myokine that potentially communicates with β-cells. At the cellular level, recombinant GDF15 protein treatment upregulated the GSIS response in β-cells by 55% (P&amp;lt;0.05), with no effect on cellular apoptosis, cytotoxicity or proliferation. Furthermore, qRT-PCR analysis, ELISA, immunoblots, and intracellular assays demonstrated that GDF15 may regulate first-phase insulin secretion by increasing the intracellular ATP/ADP ratio, inhibiting K+ channels and increasing the intracellular Ca2+ without affecting insulin synthesis. Using translational approaches, we found a positive correlation between fasting plasma GDF15 and insulin secretion in prediabetic subjects (R=0.64, P&amp;lt;0.01, n=22). A 6 week supervised functional high-intensity exercise intervention increased fasting plasma GDF15 by 35% in adults with T2D (P&amp;lt;0.01, n=12) and, interestingly, the increase in GDF15 was positively correlated with an increase in the β-cell disposition index (R=0.72, P&amp;lt;0.01, n=12), providing further support that GDF15 may be involved in improving β-cell function. In summary, these findings expand our understanding of skeletal muscle as an endocrine organ and identify GDF15 as a potential myokine for T2D therapy. Disclosure H. Zhang: None. A. Mulya: None. S. Nieuwoudt: None. R. McDowell: None. J.P. Kirwan: None.

Growth differentiation factor 15 (GDF15) is a prognosis biomarker of sequelae handicap after the occurrence of an ischemic stroke

Growth differentiation factor-15 (GDF15) is considered a poor prognosis biomarker in many cardiovascular pathological situations; however, its interest in the field of neurovascular disease such as ischemic stroke has been poorly explored so far. Our work consisted of evaluating GDF15 levels in patients hospitalized in the acute phase of ischemic stroke, who received a revascularization treatment either by fibrinolysis or thrombectomy. The main objective of our study was to evaluate the association between plasma levels of GDF15 and functional recovery at 3 months. In total, 174 patients were included between January 15th and September 30th 2017 in the University Hospital of Dijon. Biological samples were taken at the patient admission (D0) and at D1, D3 and D7. Patients were contacted by phone at 3 months in order to evaluate the Rankin score (functional disability). GDF15 plasma levels were measured by an ELISA method. In all patients, the GDF15 plasma levels at D0, D1, D3 and D7 were significantly higher in patients with a sequelae handicap (Rankin score ≥ 2) compared to patients without disabilities (Rankin score to 0 or 1). In a univariate logistic regression analysis, we found a significant increase in the odds ratio (OR) of the risk of having a Rankin score ≥ 2 with a GDF15 plasma level found in the last tertile. In addition, GDF15 levels were significantly higher in patients treated with thrombectomy than with fibrinolysis. Therefore, GDF15 appears as a relevant biomarker of poor prognosis and of sequelae handicap after ischemic stroke. Plasma levels of GDF15 being most important in patients with thrombectomy than with fibrinolysis, they may reflect the difference of the initial clinical severity, related to an occlusion of a proximal artery. Finally, after thrombectomy, GDF15 decrease could signal effective recanalization of the occluded artery.

Exercise increases circulating GDF15 in humans

ObjectiveThe growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance. Since exercise is a transient physiological stress that has pleiotropic effects on whole-body energy metabolism, we herein explored the effect of exercise on a) circulating GDF15 levels and b) GDF15 release from skeletal muscle in humans. MethodsSeven healthy males either rested or exercised at 67% of their VO2max for 1 h and blood was sampled from the femoral artery and femoral vein before, during, and after exercise. Plasma GDF15 concentrations were determined in these samples. ResultsPlasma GDF15 levels increased 34% with exercise (p < 0.001) and further increased to 64% above resting values at 120 min (p < 0.001) after the cessation of exercise. There was no difference between the arterial and venous GDF15 concentration before, during, and after exercise. During a resting control trial, GDF15 levels measured in the same subjects were unaltered. ConclusionsVigorous submaximal exercise increases circulating GDF15 levels in humans, but skeletal muscle tissue does not appear to be the source.

Plasma Growth Differentiation Factor-15 is a Potential Biomarker for Pediatric Pulmonary Arterial Hypertension Associated with Congenital Heart Disease.

We aimed to investigate plasma growth differentiation factor-15 (GDF-15) levels in pediatric pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD), and assess the association with hemodynamic parameters. Plasma GDF-15 levels were measured in children with PAH-CHD (n=46) and compared to children with CHD without PAH (n=39). Normal individuals (n=30) served as health control group. Plasma GDF-15 levels were significantly elevated in patients with PAH-CHD compared with those with CHD without PAH (median 1415ng/L, interquartile range [IQR] 926.7-2111.7ng/L vs. 890.6ng/L, IQR 394.7-1094.3ng/L, p<0.01). Elevated plasma GDF-15 levels were positively related to Functional Class, uric acid, N-terminal pro-B-type natriuretic peptide (NT-proBNP), pulmonary artery systolic pressure, mean pulmonary artery pressure, pulmonary blood flow/systemic blood flow and pulmonary vascular resistance, and a lower mixed venous oxygen saturation (Svo2). The area under the curve (AUC) for adding GDF-15 to NT-proBNP was not superior to the AUC of NT-pro BNP alone (AUC difference 0.0295, p=0.324) (NT-proBNP, AUC 0.823, 95% CI 0.725-0.897; GDF-15 plus NT-proBNP, AUC 0.852, 95% CI 0.759-0.92), whereas it revealed a slightly greater specificity and positive predictive value. The diagnostic power of NT-pro BNP was not inferior to GDF-15 (AUC difference 0.0443, p=0.43). Plasma GDF-15 levels might be a surrogate marker for pediatric PAH-CHD.

A GDF15 3' UTR variant, rs1054564, results in allele-specific translational repression of GDF15 by hsa-miR-1233-3p.

Growth differentiation factor 15 (GDF15) is a strong predictor of cardiovascular events and mortality in individuals with or without cardiovascular diseases. Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) target sites, also known as miRSNPs, are known to enhance or weaken miRNA-mRNA interactions and have been linked to diseases such as cardiovascular disease and cancer. In this study, we aimed to elucidate the functional significance of the miRSNP rs1054564 in regulating GDF15 levels. Two rs1054564-containing binding sites for hsa-miR-873-5p and hsa-miR-1233-3p were identified in the 3′ untranslated region (UTR) of the GDF15 transcript using bioinformatics tools. Their activities were further characterized by in vitro reporter assays. Bioinformatics prediction suggested that miRNA binding sites harboring the rs1054564-G allele had lower free energies than those with the C allele and therefore were better targets with higher affinities for both hsa-miR-873-5p and hsa-miR-1233-3p. Reporter assays showed that luciferase activity was significantly decreased by rs1054564-G-containing 3′ UTRs for both miRNAs (P < 0.05) and was restored by miRNA inhibitors. Comparing the fold suppression of the two miRNAs, only that of hsa-miR-1233-3p showed significant changes between the rs1054564-G- and C-containing 3′ UTRs (P = 0.034). In addition, western blots showed that transfection of both miRNA mimics significantly decreased endogenous GDF15 expression in a melanoma cell line (P < 0.05). Taken together, our findings demonstrate that GDF15 is a target of hsa-miR-873-5p and hsa-miR-1233-3p and that the rs1054564-C allele partially abolishes hsa-miR-1233-3p-mediated translational suppression of GDF15. These results suggest that rs1054564 confers allele-specific translational repression of GDF15 via hsa-miR-1233-3p. Our work thus provides biological insight into the previously reported clinical association between rs1054564 and plasma GDF15 levels.

Plasma cytokines can help to identify the development of severe acute pancreatitis on admission.

Severe acute pancreatitis (AP) is associated with high morbidity and mortality. Early severity stratification remains a challenging issue to overcome to improve outcomes. We aim to find novel plasma cytokines for the early identification of severe AP according to the revised Atlanta criteria.In this prospective observational study, 30 cytokines, screened semiquantitatively with a human multicytokine array, were submitted to quantitative determination using either microparticle-based multiplex immunoassays analyzed on a Luminex 100 platform or enzyme-linked immunosorbent assay kits. The cytokine profiles of patients and the discriminative value of cytokines for severe AP were analyzed.Plasma samples of 70 patients with AP (20 mild, 30 moderately severe, and 20 severe) were selected in this study if they were admitted within 48 hours of the onset of symptoms. Plasma from healthy volunteers was collected as the healthy control. Growth differentiation factor-15 (GDF-15) and pentraxin 3 (PTX3) on admission were independent prognostic markers for the development of severe AP and had higher discriminative powers than conventional markers (GDF-15 vs hematocrit, P = .003; GDF-15 vs C-reactive protein, P = .037; GDF-15 vs creatinine, P = .048; GDF-15 vs Acute Physiology and Chronic Health Evaluation II, P = .007; PTX3 vs hematocrit, P = .006; PTX3 vs C-reactive protein, P = .047; PTX3 vs Acute Physiology and Chronic Health Evaluation II, P = .011; PTX3 vs Bedside Index for Severity in Acute Pancreatitis, P = .048).Plasma GDF-15 and PTX3 can help to identify the development of severe AP on admission. Future work should validate their accuracy in a larger, multicenter patient cohort.

Usefulness of Elevated Levels of Growth Differentiation Factor-15 to Classify Patients With Acute Coronary Syndrome Having Percutaneous Coronary Intervention Who Would Benefit from High-Dose Statin Therapy

The aim of this study was to evaluate whether growth differentiation factor-15 (GDF-15) plasma concentration at the time of percutaneous coronary intervention (PCI) might help identify those patients with acute coronary syndrome (ACS), who benefit most from high-dose statin treatment. Two hundred eighty-four consecutive patients, who underwent percutaneous coronary intervention (PCI) for ACS, were included in a prospective registry. The combined end point at 3 months after PCI consisted of cardiovascular death, nonfatal myocardial infarction, and unstable angina. Patients were divided into those with elevated levels of GDF-15 and those with lower levels in relation to the median plasma concentration. Results were compared between patients receiving high-dose, highly efficient statins and patients receiving low-dose statins or no statins. The median GDF-15 plasma concentration was 3.31 ng/ml. One hundred six patients (74.6%) of the high GDF-15 group and 122 patients (85.9%) of the low GDF-15 group received high-dose statins. The combined end point was statistically lower in patients with high levels of GDF-15 treated with high-dose statins compared with patients treated with low-dose statins or without statin treatment (3.8% vs 22.2%, hazard ratio [HR] = 0.156; 95% confidence interval [CI], 0.047 to 0.519; p = 0.002). After propensity score adjustment, the results remained significant (adjusted HR for high-dose statins = 0.148; 95% CI, 0.045 to 0.494; p = 0.002). In contrast, in patients with lower levels of GDF-15, there was no significant reduction in combined end point rates associated with high-dose statin treatment (1.6% vs 5.0%, HR = 0.320; 95% CI 0.029 to 3.534; p = 0.353). In conclusion, increased GDF-15 plasma concentrations at the time of PCI and stent implantation might classify high-risk patients with ACS who benefit from high-dose, highly efficient statins.

GDF15 is a heart‐derived hormone that regulates body growth

The endocrine system is crucial for maintaining whole‐body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart‐derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a bona fide heart‐derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive (FTT). Together these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Our results also provide a potential mechanism for the well‐established clinical observation that children with heart diseases often develop FTT.