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.

脑组织GDF-15水平与脑梗死大鼠血管新生以及Th1/Th2免疫平衡轴的关系

目的:探讨脑组织GDF-15水平与脑梗死大鼠血管新生以及Th1/Th2免疫平衡轴的关系。方法:45只雄性SD大鼠随机分为脑梗死模型组、假手术组以及正常对照组,15只/组。模型组采用线栓法建立脑梗死模型,假手术组仅暴露颈内动脉后直接缝合皮肤,建模成功后1周评估大鼠改良神经功能缺损(mNSS)评分。采用HE染色检测脑组织病理学变化情况,Western blot法检测大鼠脑组织中组织生长分化因子-15(GDF-15)蛋白水平,RTPCR测定脑组织中GDF-15 mRNA水平。采用ELISA法检测脑组织INF-γ、IL-4表达情况,采用Spearman相关性分析大鼠脑组织中GDF-15蛋白、mRNA表达水平分别与mNSS评分、微血管密度(MVD)、INF-γ/IL-4水平之间的相关性。结果:模型组大鼠mNSS评分明显高于假手术组和正常对照组(P<0.001),模型组脑梗死面积比为(24.45±4.15)%,假手术组和正常对照组未发现脑梗死区域。模型组大鼠脑组织GDF-15蛋白、mRNA、MVD、INF-γ/IL-4水平均明显高于假手术组和正常对照组(P<0.05)。Spearman相关性分析显示,模型组大鼠脑组织中GDF-15蛋白、mRNA表达水平分别与mNSS评分、MVD、INF-γ/IL-4水平呈正相关关系(P<0.001)。结论:脑梗死大鼠脑组织中GDF-15处于高表达状态,且与神经功能密切关联,其作用机制可能与血管新生以及调控Th1/Th2免疫平衡轴有关。

急性期和亚急性期川崎病患儿血清TIMP1、GAL-3、GDF-15水平变化及临床意义

目的探讨急性期和亚急性期川崎病患儿血清基质金属蛋白酶抑制剂1(TIMP1)、血浆半乳糖凝集素-3(GAL-3)、生长分化因子(GDF-15)水平变化情况及其临床意义。方法随机选取2019年10月至2021年5月收治的川崎病患儿100例,其中急性期患儿65例,亚急性期患儿35例,比较2组川崎病患儿血清TIMP1、GAL-3、GDF-15水平,并对2组患儿免疫功能指标、炎性因子水平指标和心功能水平指标进行比较。结果急性期川崎病患儿血清TIMP1、GAL-3、GDF-15水平高于亚急性期患儿,差异有统计学意义(t=11.873、9.729、11.230,P<0.05)。急性期川崎病患儿CD3+、CD4+和CD4+/CD8+高于亚急性期患儿,CD8+水平低于亚急性期患儿,差异有统计学意义(t=15.938、4.612、13.326、10.731,P<0.05)。急性期川崎病患儿CRP、IL-6和TNF-α水平高于亚急性期患儿,差异有统计学意义(t=18.443、26.424、7.488,P<0.05)。急性期和亚急性期川崎病患儿LVSF、LVEF、CI和E/A等心功能水平指标差异无统计学意义(t=0.173、0.976、2.477、0.265,P>0.05)。结论川崎病患儿在急性期血清TIMP1、GAL-3、GDF-15水平明显升高,可考虑作为判断患儿所处时期的实验室指标,且急性期免疫功能指标、炎性因子水平指标也与亚急性期患儿存在差异,可考虑作为辅助判断指标。

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.

舒血宁注射液对急性脑梗死大鼠脑组织的保护作用及其机制

目的:探讨舒血宁注射液对急性脑梗死大鼠脑组织的保护作用,并阐明其作用机制。方法:50只大鼠随机分为对照组、假手术组、模型组、尼莫地平组和舒血宁注射液组(n=10)。模型组、尼莫地平组和舒血宁注射液组采用颈内动脉线栓法建立急性脑梗死大鼠模型。假手术组大鼠分离颈总动脉、颈外动脉和颈内动脉后,只结扎颈外动脉;对照组大鼠不作手术处理。舒血宁注射液组大鼠造模成功后给予舒血宁注射液,尼莫地平组大鼠造模后给予尼莫地平,对照组、模型组和假手术组大鼠给予等体积生理盐水。检测各组大鼠神经功能缺损评分、脑组织含水量和相对脑梗死面积,HE染色观察各组大鼠脑组织形态表现,免疫组织化学染色检测各组大鼠脑组织中生长分化因子15(GDF-15)和C反应蛋白(CRP)表达水平,ELISA法检测各组大鼠脑组织中肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)和白细胞介素1β(IL-1β)水平。结果:对照组和假手术组大鼠脑皮层结构完整,细胞排列整齐;模型组大鼠神经细胞胞浆和胞核皱缩,神经细胞与毛细管周围间质疏松;舒血宁注射液组大鼠脑皮质神经细胞、神经胶质细胞肿胀程度及间质疏松程度均减轻,病理组织形态表现与尼莫地平组相近。与对照组和假手术组比较,模型组大鼠脑组织含水量升高(P<0.05),脑组织中CRP表达水平和TNF-α、IL-6和IL-1β水平升高(P<0.05),GDF-15表达水平明显降低(P<0.05)。与模型组比较,尼莫地平组和舒血宁注射液组大鼠神经功能缺损评分降低(P<0.05),脑组织含水量明显降低(P<0.05),相对脑梗死面积减小(P<0.05),脑组织中CRP表达水平和TNF-α、IL-6及IL-1β水平均明显降低(P<0.05),GDF-15表达水平明显升高(P<0.05)。与尼莫地平组比较,舒血宁组大鼠神经功能缺损评分,脑组织含水量,相对脑梗死面积,脑组织中CRP和GDF-15表达水平及TNF-α、IL-6、IL-1β水平比较差异均无统计学意义(P>0.05)。结论:舒血宁注射液可上调急性脑梗死大鼠脑组织GDF-15表达,抑制CRP表达,降低细胞炎性因子水平,改善神经功能,对急性脑梗死起保护作用。