生长分化因子-15在心血管疾病中的临床价值

生长分化因子-15是转化生长因子-β超家族成员之一,具有抗肿瘤、抗器官损伤等细胞保护功能。生长分化因子-15属于氧化应激蛋白,在损伤心肌中大量表达。最新文献报道,生长分化因子-15对预测心力衰竭、心肌梗死预后有重要作用,现就生长分化因子-15对多种心血管疾病中的预测作用及其临床应用做一综述。     

GDF-15在心血管疾病中作用的研究进展

目前对心血管疾病(CVD)的研究发现，在病理或应激条件下，心肌细胞中生长分化因子(GDF)-15的表达和分泌增加，对抑制心脏重构及心肌凋亡起有益作用，有望成为CVD的临床治疗新靶点。而且研究表明GDF-15可预测CVD的发生发展，可作为诊断CVD及评估预后的新型生物标志物。本文就GDF-15在CVD中的作用的研究进展作一综述。     

生长分化因子15在心血管疾病中的研究进展

生长分化因子15（GDF-15）是细胞因子超家族转化生长因子-β中的成员。在生理条件下GDF-15在心肌中呈弱表达,而在诸多病理条件下其表达水平增加。越来越多的证据表明,GDF-15水平升高是心血管疾病的一种很有价值的预后标志物。此外,GDF-15对心肌细胞具有内源性抗肥厚和拮抗心脏缺血／再灌注损伤的性质。GDF-15正在成为评估和管理心脏病患者的一种很有前途的生物学标志物,并对心肌细胞具有潜在的保护作用。     

生长分化因子15与心血管疾病

生长分化因子15属于生长分化因子家族,是转化生长因子β超家族的成员之一。既往发现,生长分化因子15在风湿性关节炎、炎症、肿瘤、贫血等情况下表达增加,近年发现生长分化因子15的增高与心力衰竭、急性冠状动脉综合征、原发性肺动脉高压等疾病密切相关,在心衰及其他心血管疾病中独立反映疾病预后,可能是心血管系统中一个新的生物标志物。     

院前负荷剂量阿托伐他汀钙对ST段抬高急性心肌梗死患者生长分化因-15、BNP、cTNI的影响

目的观察院前给予急性心肌梗死患者负荷剂量阿托伐他汀钙对血浆生长分化因子-15、脑钠肽(BNP)、心肌钙蛋白I(cTNI)等的影响。方法将2012年5月—2013年5月急性心肌梗死成功PCI患者93例,随机分组,在接受常规治疗基础上,研究组(47例)在院前急救车上给予负荷剂量阿托伐他汀钙20mg,并术后每晚常规服用20mg阿托伐他汀钙;对照组(46例)为术后常规每晚给予阿托伐他汀钙40mg。观察生长分化因子-15、BNP、cTNI水平的变化。结果与对照组相比,研究组生长分化因子-15、BNP、TNI水平明显高于对照组。结论院前早期给予负荷剂量阿托伐他汀钙可以显著降低血清生长分化因-15、BNP、cTNI水平。     

生长分化因子-15在心血管疾病的研究进展

生长分化因子-15是转化生长因子-超家族的成员之一.既往研究表明,生长分化因子-15主要参与调节多器官生长、分化及组织修复等生物学过程.近年研究发现生长分化因子-15水平增高与急性冠脉综合征、心力衰竭等心血管疾病相关,并可能发挥保护性作用.     

microRNAs在心肌肥厚中的作用

生理或病理性刺激会导致心肌肥厚性生长,表现为心肌细胞增大,蛋白合成增加及胎儿基因的再表达。在心脏中有很多信号分子影响着基因表达、细胞凋亡、细胞因子释放等病理生理过程。利用心肌细胞肥厚模型已经发现病理性心肌肥厚可以被抑制或逆转,这些发现为寻找调控心肌肥厚的因子及信号通路提供了基础。该文着重讨论近年来发现的microRNAs(miRNAs)在调节心肌肥厚中的作用。     

生长分化因子15与心血管疾病的研究进展

生长分化因子15（growthdifferentiationfactor15,GDF15）是转化生长因子-β（TGF-β）超家族成员之一,GDF15参与了肿瘤的发生和发展,调控肿瘤的生长,抑制肿瘤的转移。近来研究发现,GDF15还是一个重要的心血管保护因子,与心血管系统疾病密切相关,现将其研究进展综述如下。     

生长分化因子-15与心血管疾病

生长分化因子-15(GDF-15)是转化生长因子β超家族的远支成员。高水平GDF-15提示冠状动脉粥样硬化性心脏病(冠心病)患病风险较高。在冠心病、心房颤动、心力衰竭、先天性心脏病等心血管疾病中,高水平GDF-15提示预后较差。GDF-15可能通过参与动脉粥样硬化形成、保护梗死后心肌、抑制血栓形成等机制在心血管疾病的发生发展中发挥重要作用。     

AMPK与心肌缺血-再灌注损伤

心肌缺血-再灌注损伤是急性心肌梗死后溶栓疗法、经皮冠状动脉介入治疗、冠状动脉旁路移植术后心肌损伤的重要机制之一。单磷酸腺苷激活的蛋白激酶(AMPK)不仅是细胞内能量代谢的重要调控因子,而且能通过抗氧化应激、内质网应激、抑制凋亡、调节自噬、抗炎、参与缺血预处理或缺血后处理等心肌保护效应减轻心肌缺血-再灌注损伤。因此,AMPK对防治心肌缺血-再灌注损伤有潜在的临床意义。     

The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury

Data from the Women's Health Study show that serum levels of growth-differentiation factor-15 (GDF-15), a distant member of the transforming growth factor-beta superfamily, are an independent risk indicator for adverse cardiovascular events. However, the cellular sources, upstream regulators, and functional effects of GDF-15 in the cardiovascular system have not been elucidated. We have identified GDF-15 by cDNA expression array analysis as a gene that is strongly upregulated by nitrosative stress in cultured cardiomyocytes isolated from 1- to 3-day-old rats. GDF-15 mRNA and pro-peptide expression levels were also induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO-peroxynitrite-dependent signaling pathways. GDF-15 was actively secreted into the culture supernatant, suggesting that it might exert autocrine/paracrine effects during I/R. To explore the in vivo relevance of these findings, mice were subjected to transient or permanent coronary artery ligation. Myocardial GDF-15 mRNA and pro-peptide abundance rapidly increased in the area-at-risk after ischemic injury. Similarly, patients with an acute myocardial infarction had enhanced myocardial GDF-15 pro-peptide expression levels. As shown by immunohistochemistry, cardiomyocytes in the ischemic area contributed significantly to the induction of GDF-15 in the infarcted human heart. To delineate the function of GDF-15 during I/R, Gdf-15 gene-targeted mice were subjected to transient coronary artery ligation for 1 hour followed by reperfusion for 24 hours. Gdf-15-deficient mice developed greater infarct sizes and displayed more cardiomyocyte apoptosis in the infarct border zone after I/R compared with wild-type littermates, indicating that endogenous GDF-15 limits myocardial tissue damage in vivo. Moreover, treatment with recombinant GDF-15 protected cultured cardiomyocytes from apoptosis during simulated I/R as shown by histone ELISA, TUNEL/Hoechst staining, and annexin V/propidium iodide fluorescence-activated cell sorting (FACS) analysis. Mechanistically, the prosurvival effects of GDF-15 in cultured cardiomyocytes were abolished by phosphoinositide 3-OH kinase inhibitors and adenoviral expression of dominant-negative Akt1 (K179M mutation). In conclusion, our study identifies induction of GDF-15 in the heart as a novel defense mechanism that protects from I/R injury.     

Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction.

AIMS: Growth-differentiation factor-15 (GDF-15) is a transforming growth factor-beta-related cytokine that is induced in the heart following ischaemia-reperfusion injury. We explored the prognostic utility of GDF-15 in patients with ST-segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy. METHODS AND RESULTS: Circulating levels of GDF-15 were determined by an immunoradiometric assay in 741 STEMI patients who were included in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-2 and ASSENT-plus trials. About 72.7% of the patients presented with GDF-15 levels > or =1200 ng/L, the upper limit of normal in apparently healthy elderly individuals. Increased levels of GDF-15 were associated with a higher risk of death during 1-year follow-up. Mortality rates at 1 year were 2.1, 5.0, and 14.0% in patients with GDF-15 levels <1200, 1200-1800, and >1800 ng/L, respectively (P < 0.001). GDF-15 remained an independent predictor of mortality after adjustment for clinical variables, troponin T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). GDF-15 provided prognostic information in clinically relevant patient subgroups, defined according to age, gender, cardiovascular risk factors, haemodynamic status, and the TIMI risk score. Moreover, GDF-15 added prognostic information to the established biomarkers of adverse prognosis in STEMI, troponin T, and NT-proBNP. CONCLUSION: GDF-15 is a new biomarker in STEMI that provides prognostic information beyond established clinical and biochemical markers.     

心肌纤维化因子sST2、GDF-15、GAL-3表达与急性心肌梗死的相关性

目的：探索血浆中表达心肌纤维化因子sST2、GDF-15、GAL-3与急性心肌梗死的相关性。方法：纳入同期住院的急性冠脉综合征患者,以UA（N=75）为对照,检测AMI患者(N=78)血浆中sST2、GDF-15、GAL-3的表达变化,分析其与急性冠脉综合征类型的相关性及三者间的相互关系。结果：与UA组相比,AMI组患者血浆sST2水平更高,且与心梗后CK峰值呈正相关,而两组患者血浆GDF-15、GAL-3水平无明显差异;血浆GDF-15与sST2表达水平呈弱相关（r=0.348）,GAL-3与之不相关（r=0.146）,GDF-15与GAL-3水平呈显著相关（r=0.518,P＜0.001）。结论：心肌纤维化因子sST2表达与急性心肌梗死密切相关。     

Relation of growth-differentiation factor 15 to left ventricular remodeling in ST-segment elevation myocardial infarction

The development of left ventricular remodeling (LVR) after myocardial infarction is associated with a high risk of heart failure and death. LVR is difficult to predict, and limited information is available on the association of cardiac biomarkers and LVR. Growth-differentiation factor-15 (GDF-15) is induced during heart failure development and, in animals models, might influence the different processes involved in cardiac remodeling. The aim of the present investigation was to assess the association between the serum levels of GDF-15 within the first 24 hours of ST-segment elevation myocardial infarction and the development of subsequent LVR at 12 months of follow-up. This prospective study included 97 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Echocardiography was performed in all patients within the first 96 hours of admission and at 12 months of follow-up. LVR was defined as a >20% increase in the left ventricular end-diastolic volume at 12 months of follow-up compared to baseline. Blood samples for the determination of GDF-15 and brain natriuretic peptide were obtained within the first 24 hours after symptom onset. According to the pre-established criteria, 21 patients (22%) had LVR. Patients with LVR had greater levels of GDF-15 at study entry (median 3,439 pg/ml, interquartile range 2,391 to 6,168 vs median 1998 pg/ml, interquartile range 1,204 to 3,067, respectively; p <0.001). Multivariate analysis showed that GDF-15 (odds ratio 10.1, 95% confidence interval 2.5 to 40.1, p <0.001) and treatment with angiotensin-converting enzyme inhibitors (odds ratio 3.9, 95% confidence interval 1.2 to 12.3, p <0.01) were independents predictors of LVR. Receiving operating characteristics analysis showed an area under the curve of 0.77 for GDF-15 (95% confidence interval 0.67 to 0.84, p <0.001). In conclusion, the results of the present study have identified GDF-15 as an independent marker of LVR in patients with ST-segment elevation myocardial infarction.     

Prevalence,characteristics, and risk stratification of electrocardiographic and symptomatic silence of myocardial ischemia despite scintigraphically evidenced ischemia in symptomatic patients presenting with severe coronary artery stenosis

Symptoms of angina pectoris and transient ST-segment depression are most commonly used to evidence acute myocardial ischemia during exercise testing. However, the diagnostic accuracy of either or both criteria in relation to clinical characteristics and the patient's exercise response has been a subject of controversy. The prevalence and severity of symptoms of angina pectoris and/or ST-segment depression were studied prospectively in 147 consecutive patients with a history of daily angina pectoris, scintigraphic evidence of exercise-induced myocardial ischemia, and coronary artery stenosis >75%. Logistic regression analysis was applied to determine absence of any or both criteria by the clinical characteristics or exercise response of the patient. During exercise testing, ST-segment response failed to prove scintigraphically evidenced myocardial ischemia in 14/147 patients (10%) and 35/147 patients (24%) when ST-segment depression ≥0.1 in either ≥1 or ≥2 ECG leads was chosen. Symptoms of angina pectoris were found to be absent in 69/147 patients (47%). Only 58 patients (40%) suffered from angina and met the ECG criterion at the time of scintigraphic myocardial ischemia. Absence of ST-segment depression was best predicted by clinical variables such as large myocardial infarction (increase: 2.6 times, p = 0.007), number of stenoses ≥2 (2.0 times, p = 0.023), and presence of diabetes mellitus (4.3 times, p = 0.035). Painless myocardial ischemia was only determined by blood response to exercising. Thus, a double product > 23 increased the risk of painless myocardial ischemia by 1.5 times (p = 0.017). In multivariate analysis, only blood pressure response, infarction size, and the number of diseased vessels were found to be independent predictors of the absence of angina pectoris or ST-segment depression during myocardial ischemia.     

非心脏手术围手术期心肌缺血与心脏事件的相关因素

明确与围手术心肌缺血之相关因素及手术后心脏事件发生的关系,以期提出预防措施,减少围手术期心脏事件的发生。方法 观察102例老年患者围手术期有无心肌缺血及心脏事件发生。结果 发生围手术期缺血有38例,86.8%表现为无症状心肌缺血,仅5例（13.2%）有症状。患有糖尿病、原发性高血压、心绞痛、有心衷病史的患者围手术期缺血发生明显增高。有糖尿病患者高3.5倍,有心衰者高5.4倍。有围手术期缺血的患者发生围手术期心脏并发症的比例明显增高（高11倍）。结论 围手术期心肌缺血是围手术期心及事件发生的预警指标：围手术期心肌缺血（包括心肌梗死）大部分为无症状心肌缺血;有心绞痛和心衰病史的患者围手术期心肌缺血的发生明显增高。     

超声心动图负荷试验评价冠状动脉再通治疗后心肌缺血

为评价冠心病患者冠状动脉（冠脉）再通治疗后的心肌缺血，对57例冠脉扩张或冠脉搭桥术后有胸痛等症状的病人进行超声心动图多巴酚丁胺或运动负荷试验（DSE／TMX）。结果：DSE／TMX阳性提示心肌缺血者26例，占45．6％，均无严重并发症发生。10例再行冠脉造影，6例DSE／TMX阳性者中，5例相应血管严重狭窄，1例相应血管轻微病变，4例DSE／TMX阴性者中，2例冠脉造影示相应血管亦无严重狭窄。表明：DSE／TMX可用于筛选划分需再次行血管再通治疗及需加强扩张冠脉药物治疗的病人，也可用于筛选冠脉再通治疗后心肌缺血的低危病人群。DSE／TMX是安全有效的心肌缺血评价手段。     

老年急性冠脉综合征患者血清生长分化因子-15的表达及其临床意义

目的观察生长分化因子-15(GDF-15)在老年急性冠脉综合征(ACS)患者血清中的变化及其对近期预后的预测价值。方法选取老年ACS患者116例,分为急性心肌梗死(AMI)组46例,不稳定型心绞痛(UAP)组70例,同时设同期因胸痛、胸闷症状入院经冠脉造影排除冠心病的对照组40例。采集空腹外周血,采用酶联免疫法测定患者血清GDF-15浓度。对ACS患者随访6月,记录其心血管不良事件的发生情况。结果 AMI组GDF-15水平为(815.41±227.54)ng/L,显著高于UAP组[(735.06±144.94)ng/L,P0.05]与对照组[(641.97±143.90)ng/L,P0.01]。同时UAP组与对照组GDF-15水平比较差异也有统计学意义(P0.01)。发生心血管事件组GDF-15水平高于未发生心血管事件组(P0.01)。结论 GDF-15水平在老年ACS患者中明显升高,其升高程度与ACS的类型有关,GDF-15可作为判断老年ACS近期预后的指标。     

心肌缺血负荷值评价不同部位心肌梗死后心肌缺血的临床价值

目的：探讨用心肌缺血负荷值评价不同部位心肌梗死后心肌缺血的临床价值。方法：采用美国Marquete 24h三通道磁带记录盒连续动态心电监测,对368例心肌梗死后患进行ST段分析。结果：108例心肌梗死后Holter检出心肌缺血,检出率29．3％,108例中共1226次心肌缺血,其中无症状心肌缺血占98．85％,不同部位心肌梗死的心肌缺血负荷值无显差异,昼夜心肌缺血负荷值无显差异。结论：心肌缺血负荷值是分析比较ST段改变的一个准确的量化指标,能有效的检出不同部位心肌梗死后心肌缺血的程度,为临床对心肌硬死后心肌缺血的疗效观察提供有效的量化指标。