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-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.

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。

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.

CHF患者GDF-15、NT-proBNP水平的检测意义

目的探讨不同程度慢性心力衰竭(chronic heart failure,CHF)患者血浆生长分化因子-15(growth differentiation factor-15,GDF-15)及氮末端-前体脑钠肽(N-terminal pro-brain natriuretic peptide,NT-proBNP)的表达水平的检测意义。方法选择本院于2018年1月—2019年12月期间收治的慢性心力衰竭患者80例作为观察组,另选择健康体检无器质性心脏病者80例作为对照组,均行GDF-15、NT-proBNP检测,比较观察组与对照组检测结果,不同心功能分级患者检测结果。结果观察组GDF-15、NT-proBNP水平显著高于对照组,P<0.05;心衰失代偿组GDF-15、NTproBNP显著高于心衰代偿组,P<0.05。结论在慢性心力衰竭病情发现及发展评估中可行GDF-15、NT-proBNP检测,依据指标水平变化可明确诊断、评估病情及预后,为临床诊断治疗提供可靠依据,研究价值较高。

精浆中GDF-15对妊娠结局的影响

目的比较人工授精(IUI)与自然妊娠之间妊娠结局的差异,探讨男性精浆在早期妊娠中的作用。方法收集2015年1月-2017年12月于本院生殖医学科就诊的326例妊娠患者数据,其中经IUI妊娠者190例,自然妊娠者136例。比较IUI和自然妊娠之间早期妊娠丢失率、中晚期流产率以及活产率的差异,并探讨精浆中生长分化因子15(GDF-15)对子宫内膜容受性的影响。结果IUI妊娠组与自然妊娠组在早期妊娠丢失率(34.73%vs.22.06%)和活产率(61.17%vs.75.19%)方面存在统计学差异(P均<0.05),OR值分别为1.88(95%CI:1.14~3.11)和0.52(95%CI:0.32~0.85)。进一步体外实验显示:rhGDF-15可以上调小鼠子宫内膜中LIF、Integrinανβ3和HOXA 11基因的表达。结论精浆因素可能是导致IUI与自然妊娠之间妊娠结局差异的原因;精浆中GDF-15对子宫内膜容受性有潜在的益处。

血浆生长分化因子15在帕金森中的诊断价值及与临床分期的相关性研究

目的 探讨血浆生长分化因子15(Growth differentiation factor 15,GDF-15)在帕金森中的诊断价值及与临床分期的相关性。方法 选择2020年10月至2021年6月期间徐州医科大学附属医院的60例PD患者作为研究组,另外选择于徐州医科大学附属医院体检中心进行体检的100例健康者作为对照组。对照组与研究组入选对象于清晨空腹状态下抽取静脉血。GDF-15水平采用酶联免疫吸附法进行测定分析。比较对照组与研究组血浆GDF-15水平、MMSE及MoCA评分、PD患者MMSE及MoCA评分与血浆GDF-15水平相关性。结果 (1)研究组血浆GDF-15水平显著高于对照组,且随着病情的加重,患者血浆GDF-15水平显著升高(P均<0.05);(2)研究组MMSE及MoCA评分显著小于对照组,且随着病情的加重,患者MMSE及MoCA评分显著下降(P均<0.05);(3)经相关性分析,PD患者MMSE及MoCA评分与血浆GDF-15水平呈负相关性(r值分别为-0.9165、-0.7645,P均<0.05)。结论血浆GDF-15对PD具有一定的临床诊断价值,其与H-Y分期呈正相关性,与神经功能评分呈负相关性,能够为PD的临床诊疗提供一定的依据。

血浆生长分化因子-15在慢性阻塞性肺疾病严重程度及预后预测中的价值

目的通过测定慢性阻塞性肺疾病(COPD)患者血浆生长分化因子(GDF-15)的水平,探讨GDF-15在COPD严重程度分级和判断预后中的作用。方法纳入2014年4月~2019年2月我院收治的99例COPD住院患者作为COPD组,按严重程度分为中度组(n=35)、重度组(n=33)、极重度组(n=31),记录各组的基线资料,并对相关指标进行比较。对COPD患者进行14个月随访,记录COPD不良事件。采用Spearman相关分析研究COPD中度、重度、极重度的GDF-15和CRP之间的相关性。并比较GDF-15和CRP区分对照组和COPD组的诊断效能,预测COPD组不良事件。结果与对照组相比,COPD组患者CRP、GDF-15水平明显升高,CRP、GDF-15随COPD严重程度增加而明显升高(均P<0.05),在中度组COPD患者中,血浆中GDF-15与CRP浓度呈正相关(r=0.952,P<0.001),在重度组COPD患者中,血浆中GDF-15与CRP浓度呈正相关(r=0.951,P<0.001),在极重度组COPD患者中,血浆中GDF-15与CRP浓度呈正相关(r=0.973,P<0.001)。ROC曲线表明,血浆CRP、GDF-15对COPD诊断的AUC分别为0.764、0.900,最佳诊断临界值分别为10.45 mg/L、485.50 ng/mL。CRP、GDF-15二者联合诊断的AUC为0.091,血浆CRP、GDF-15对COPD不良事件预测的AUC分别为0.855、0.859,最佳诊断临界值分别为18.45 mg/L、720.95 ng/mL。CRP、GDF-15二者联合诊断的AUC为0.864。结论GDF-15和CRP均有助于判断COPD的严重程度,对预测患者病情的严重程度和预后有着积极的临床意义。