Correlation between growth differentiation factor-15 and collagen metabolism indicators in patients with myocardial infarction and heart failure

BackgroundGrowth differentiation factor （GDF）-15, a divergent member of the transforming growth factor beta super-family does appear to be up-regulated in response to experimental pressure overload and progression of heart failure （HF）. HF frequently develops after myocardial infarction （MI）, contributing to worse outcome. The aim of this study is to assess the correlation between GDF-15 levels and markers related to collagen turnover in different stages of HF.MethodsThe study consists of a cohort of 179 patients, including stable angina pectoris patients （AP group,n= 50）, old MI patients without HF （OMI group,n = 56）, old MI patients with HF （OMI-HF group,n= 38） and normal Control group （n = 35）. Both indicators reflecting the synthesis and degradation rates of collagen including precollagen I N-terminal peptide （PINP）, type I collagen carboxy-terminal peptide （ICTP）, precollagen III N-terminal peptide （PIIINP） and GDF-15 were measured using an enzyme-linked inmunosorbent assay.ResultsThe plasma GDF-15 level was higher in OMI-HF group （1373.4 ± 275.4 ng/L） than OMI group （1036.1 ± 248.6 ng/L）, AP group （784.6 ± 222.4 ng/L） and Control group （483.8 ± 186.4 ng/L） （P〈 0.001）. The indi-cators of collagen turnover （ICTP, PINP, PIIINP） all increased in the OMI-HF group compared with Control group （3.03 ± 1.02μg/Lvs. 2.08 ± 0.95μg/L, 22.2 ± 6.6μg/Lvs. 16.7 ± 5.1μg/L and 13.2 ± 7.9μg/Lvs. 6.4 ± 2.1μg/L, respectively;P〈 0.01）. GDF-15 positively cor-related with ICTP and PIIINP （r = 0.302,P〈 0.001 andr= 0.206,P= 0.006, respectively）. GDF-15 positively correlated to the echocardio-graphic diastolic indicators E/Em and left atrial pressure （r= 0.349 and r= 0.358, respectively;P〈 0.01）, and inversely correlated to the systolic indicators left ventricular ejection fraction and the average of peak systolic myocardial velocities （Sm） （r=-0.623 and r=-0.365, respectively;P〈 0.01）.ConclusionPlasma GDF-15 is associated with the indicators of type I and III collagen turnover.

Growth differentiation factor-15 is a prognostic marker in patients with intermediate coronary artery disease

Background Growth differentiation factor-15(GDF-15)is involved in multiple processes that are associated with coronary artery disease(CAD).However,little is known about the association between GDF-15 and the future ischemic events in patients with intermediate CAD.This study was conducted to investigate whether plasma GDF-15 constituted risk biomarkers for future cardiovascular events in patients with intermediate CAD.Methods A prospective study was performed based on 541 patients with intermediate CAD(20%–70%).GDF-15 of each patient was determined in a blinded manner.The primary endpoint was major adverse cardiac event(MACE),which was defined as a composite of all-cause death,nonfatal myocardial infarction,revascularization and readmission due to angina pectoris.Results After a median follow-up of 64 months,504 patients(93.2%)completed the follow-up.Overall,the combined endpoint of MACE appeared in 134 patients(26.6%)in the overall population:26 patients died,11 patients suffered a nonfatal myocardial infarction,51 patients underwent revascularization,and 46 patients were readmitted for angina pectoris.The plasma levels of GDF-15(median:1172.02 vs.965.25 pg/m L,P=0.014)were higher in patients with ischemic events than those without events.After adjusting for traditional risk factors,higher GDF-15 levels were significantly associated with higher incidence of the composite endpoint of MACE(HR=1.244,95%CI:1.048–1.478,Quartile 4 vs.Quartile 1,P=0.013).Conclusions The higher level of GDF-15 was an independent predictor of long-term adverse cardiovascular events in patients with intermediate CAD.

Growth Differentiation Factor-9 Gene Expression of Mice Oocytes in Vitro and in Vivo

Mice preantral follicles were cultured in vitro for 12 days to achieve metaphase Ⅱ （M Ⅱ ） oocytes. Oocyte growth differentiation factor-9 （GDF-9） gene expression was measured during different growth stages to explore the relationship between oocyte maturation and GDF-9 gene expression. Preantral follicles of lO-day old mice were isolated from the ovaries and were cultured for 12 days. Oocytes from day 2 （D2）, D4, D6, D8, DIO, D12 cultured in vitro were named the in vitro group and oocytes of day 12 （D12）, D14, D16, D18, D20, D22 grown in vivo were named the in vivo group. Follicle survival, antrum formation and maturation rate were 89.5%, 51.8% and 56.6% respectively in follicles cultured in vitro. After RT-PCR and agarose gel electrophoresis, relative mRNA abundance of GDF-9 was measured in each group of oocytes. At day 8 - 12, the GDF-9 gene expression level of oocytes in vitro was significantly lower than that in vivo （P 〈 0.05）. We conclude that M Ⅱ oocytes can be obtained from in vitro culture of preantral follicles. The GDF- 9 gene expression of oocytes varies at different growth stages in vivo. The low expression of GDF-9 in oocytes cuhured in vitro may be the cause of their low developmental capacity.

2型糖尿病肾病患者生长分化因子-15的表达及临床意义

目的：探讨生长分化因子-15（GDF-15）在2型糖尿病肾病中的表达水平及其临床意义。方法纳入80例2型糖尿病（T2DM）患者，根据Mogensen分期标准，分为正常白蛋白尿组（30例）、微量白蛋白尿组（20例）和大量白蛋白尿组（30例），采用ELISA法测定血浆GDF-15水平。结果大量白蛋白尿组GDF-15水平高于微量白蛋白尿组和正常白蛋白尿组（P均＆lt;0.01），分别为1773.9（1099.1-2357.4）pg/ml、864.0（636.1-994.3）pg/ml和704.5（548.8-975.8）pg/ml；微量白蛋白尿组GDF-15水平高于正常白蛋白尿组（P＆gt;0.05），且在肾功能轻度受损（60≤肾小球滤过率＆lt;90 ml/min/1.73 m2）时GDF-15浓度即有增加，为999.5（769.2-1372.1）pg/ml。偏相关分析显示，血浆GDF-15与糖尿病病程、尿微量白蛋白（mAlb）、尿素氮（BUN）及肌酐（sCr）呈正相关（r=0.246，0.493，0.390，0.471，P均＆lt;0.05），与估计的肾小球滤过率（eGFR）及血浆白蛋白（Alb）呈负相关（r=-0.438，-0.397，P均＆lt;0.01）。多元线性回归分析提示较高水平的GDF-15为mAlb增加的独立危险因素。在对肾功能受损（eGFR＆lt;90 ml/min/1.73 m2）的诊断中，GDF-15和mAlb的曲线下面积分别为0.801和0.717，GDF-15曲线下面积大于mAlb（P＆lt;0.05）。当733.78 pg/ml作为GDF-15诊断肾功能受损的临界值时，敏感性和特异性达到最佳，分别为88.1%和58.1%。结论GDF-15在2型糖尿病肾病不同临床阶段有不同程度的增高，不但与mAlb、eGFR有良好的相关性，而且是mAlb增加的独立危险因素，故在2型糖尿病肾病的早期诊断、病情评估及预测其疾病转归方面具有一定的应用价值。

充血性心力衰竭患者血浆生长分化因子-15水平变化及临床意义

目的观察充血性心力衰竭（CHF）患者血浆生长分化因子（GDF）-15 水平的变化,并探讨其临床意义.方法选取CHF 患者100 例（心衰组）和健康体检者30 例（对照组）;心衰组按美国纽约心脏病协会（NYHA）心脏功能分级分为NYHAⅡ级组35 例、Ⅲ级组32 例、Ⅳ级组33 例,按左室射血分数（LVEF）水平分为LVEF〈0.4 组52 例和LVEF≥0.4 组48 例.采用ELISA 法检测血浆GDF-15、B 型利钠肽（BNP）水平,常规超声心动图测定LVEF、左室舒张末期内径（LVDd）、收缩末期内径（LVDs）及左室短轴缩短率（LVFS）,分析GDF-15 与NYHA 分级、BNP 及超声心动图各指标的相关性.结果与对照组相比,NYHAⅡ~Ⅳ级组BNP、GDF-15、LVDd、LVDs 基本呈升高趋势,LVEF、LVFS 基本呈下降趋势（P〈0.05）.对照组、LVEF≥0.4 组和LVEF〈0.4 组BNP、GDF-15、LVDd、LVDs 依次升高,LVFS 依次降低,组间多重比较差异均有统计学意义（均P〈0.05）.血浆GDF-15 水平与BNP、NYHA 分级、LVDd、LVDs 呈正相关（r=0.524、0.286、0.453、0.531,均P 〈 0.05）,与LVEF、LVFS 呈负相关（r= -0.592、-0.587,均P 〈0.05）.结论血浆GDF-15 可作为CHF 诊断、治疗、判断预后的又一新指标.

人血清生长分化因子15与冠心病患者慢性心力衰竭的相关性研究

目的 探讨生长分化因子15（GDF-15）与冠心病患者慢性心力衰竭的关系及诊断价值.方法 选择复旦大学附属华山医院心内科269例行冠状动脉造影（CAG）检查的患者,根据CAG、心电图及心肌酶学检查结果分为3组：其中冠心病心肌梗死患者98例（MI组）,本组再根据纽约心脏病协会（NYHA）心功能分级Ⅰ～Ⅳ级分为4个亚组;未经历心肌梗死的冠心病患者84例（CAD组）;CAG正常患者87例（对照组）.采用酶联免疫吸附法测定患者GDF-15浓度.分析GDF-15与NYHA分级和血清N末端脑钠肽原（NT-proBNP）的关系.结果 MI组平均及其各不同心功能分级亚组[纽约心脏病协会（NYHA）Ⅰ级、Ⅱ级、Ⅲ级、Ⅳ级]、CAD组血清GDF-15浓度明显高于对照组,差异有统计学意义[1 622（888,1 995）,983 （808,1 501）、1 614（810,1 825）、1 940（1 837,2 063）、3 905（3 690,4 019）,945（856,1 000） ng/L比798 （728,873） ng/L] （P ＜0.05）.MI组平均及其各不同心功能分级亚组（NYHA Ⅰ级、Ⅱ级、Ⅲ级、Ⅳ级）血清NT-proBNP浓度明显高于对照组,差异有统计学意义[564（158,857）,233（105,552）、278（133,716）、790（636,1 490）、4 665（3 712,5 442） ng/L比121（108,134）ng/L] （P ＜0.05）.相关性分析显示GDF-15水平与血清NT-proBNP水平呈显著正相关（r=0.861,P＜0.01）,与血清LVEF呈显著负相关（r=-0.936,P＜0.01）.GDF-15与NT-proBNP对慢性心力衰竭的受试者工作特征曲线结果显示其下面积分别为0.804、0.795（P ＜0.01）.GDF-15的最佳临界值为1 086.38 ng/L时,对慢性心力衰竭诊断的敏感性为72.4％,特异性为93.6％.结论 GDF-15是一个新的冠心病患者慢性心力衰竭预后诊断标志物,能够对心力衰竭的严重程度进行客观评价.

Growth differentiation factor-15 combined with N-terminal prohormone of brain natriuretic peptide increase 1-year prognosis prediction value for patients with acute heart failure: a prospective cohort study

Background:Clinical assessment and treatment guidance for heart failure depends on a variety of biomarkers.The objective of this study was to investigate the prognostic predictive value of growth differentiation factor-15(GDF-15)and N-terminal prohormone of brain natriuretic peptide(NT-proBNP)in assessing hospitalized patients with acute heart failure(AHF).Methods:In total,260 patients who were admitted for AHF in the First Affiliated Hospital of Nanjing Medical University were enrolled from April 2012 to May 2016.Medical history and blood samples were collected within 24 h after the admission.The primary endpoint was the all-cause mortality within 1 year.The patients were divided into survival group and death group based on the endpoint.With established mortality risk factors and serum GDF-15 level,receiver-operator characteristic(ROC)analyses were performed.Cox regression analyses were used to further analyze the combination values of NT-proBNP and GDF-15.Results:Baseline GDF-15 and NT-proBNP were significantly higher amongst deceased than those in survivors(P<0.001).In ROC analyses,area under curve(AUC)for GDF-15 to predict 1-year mortality was 0.707(95%confidence interval[CI]:0.648–0.762,P<0.001),and for NT-proBNP was 0.682(95%CI:0.622–0.738,P<0.001).No statistically significant difference was found between the two markers(P=0.650).Based on the optimal cut-offs(GDF-15:4526.0 ng/L;NT-proBNP:1978.0 ng/L),the combination of GDF-15 and NT-proBNP increased AUC for 1-year mortality prediction(AUC=0.743,95%CI:0.685–0.795,P<0.001).Conclusions:GDF-15,as a prognostic marker in patients with AHF,is not inferior to NT-proBNP.Combining the two markers could provide an early recognition of high-risk patients and improve the prediction values of AHF long-term prognosis.Clinical trial registration:ChiCTR-ONC-12001944,http://www.chictr.org.cn.

Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons

Growth differentiation factor 15(GDF-15)is a member of the transforming growth factor-βsuperfamily.It is widely distributed in the central and peripheral nervous systems.Whether and how GDF-15 modulates nociceptive signaling remains unclear.Behaviorally,we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats.Electrophysiologically,we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia(DRG)neurons.Furthermore,GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents,and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction.GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels,suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel.Immunohistochemistry results showed that activin receptor-like kinase-2(ALK2)was widely expressed in DRG medium-and small-diameter neurons,and some of them were Nav1.8-positive.Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors.Inhibition of PKA and ERK,but not PKC,blocked the inhibitory effect of GDF-15 on Nav1.8 currents.These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK,which mediate the peripheral analgesia of GDF-15.

Eff ects of early standardized enteral nutrition on preventing acute muscle loss in the acute exacerbation of chronic obstructive pulmonary disease patients with mechanical ventilation

BACKGROUND:To investigate the eff ects of early standardized enteral nutrition(EN)on the crosssectional area of erector spine muscle(ESMcsa),plasma growth diff erentiation factor-15(GDF-15),and 28-day mortality of acute exacerbation of chronic obstructive pulmonary disease(AECOPD)patients with invasive mechanical ventilation(MV).METHODS:A total of 97 AECOPD patients with invasive MV were screened in the ICUs of the First People's Hospital of Lianyungang.The conventional EN group(stage Ⅰ)and early standardized EN group(stage Ⅱ)included 46 and 51 patients,respectively.ESMcsa loss and GDF-15 levels on days 1 and 7 of ICU admission and 28-day survival rates were analyzed.RESULTS:On day 7,the ESMcsa of the early standardized EN group was significantly higher than that of the conventional EN group,while the plasma GDF-15 levels were significantly lower than those in the conventional EN group(ESMcsa:28.426±6.130 cm^(2) vs.25.205±6.127 cm^(2);GDF-15:1661.608±558.820 pg/mL vs.2541.000±634.845 pg/mL;all P<0.001).The 28-day survival rates of the patients in the early standardized EN group and conventional EN group were 80.40%and 73.90%,respectively(P=0.406).CONCLUSION:ESMcsa loss in AECOPD patients with MV was correlated with GDF-15 levels,both of which indicated acute muscular atrophy and skeletal muscle dysfunction.Early standardized EN may prevent acute muscle loss and intensive care unit-acquired weakness(ICU-AW)in AECOPD patients.