CN113884586A - 一种特发性肺动脉高压的预后标记物及其应用 - Google Patents
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Abstract
本发明涉及生物医药领域,具体涉及一种特发性肺动脉高压(IPAH)的预后标记物及其应用。该特发性肺动脉高压的预后标记物为DHA。本发明首次发现游离脂肪酸水平与疾病严重程度相关,特别地发现较低水平的DHA预示着IPAH患者存活率低,为制备IPAH预后预测试剂盒、改善IPAH预后的药物以及治疗IPAH的药物提供了策略。
Description
技术领域
本发明涉及生物医药领域,具体涉及一种特发性肺动脉高压的预后标记物及 其应用。
背景技术
特发性肺动脉高压(IPAH)是一种罕见但自然预后极差的疾病,其特征是 肺小动脉血管重塑,导致肺血管阻力(PVR)增加,右心室肥大,最终导致右心 衰竭。IPAH的发病率约为6/100万,病死率高,从症状出现到诊断的平均时间 为2年,中位生存期为2.8年,1年、3年和5年生存率分别为68%、48%和34%。 由于IPAH缺乏特征性的临床症状和体征,很容易被误诊。当疾病被确诊时,往 往已经进展到中期或更严重的阶段,预后不良,药物治疗疗效不佳。此外,IPAH 病理生理学机制复杂,IPAH患者中的血管细胞(内皮细胞、平滑肌细胞和成纤 维细胞)和炎性细胞异常增殖、凋亡抵抗或聚集。遗传、表观遗传失调、自身免 疫性、炎性疾病、右心室缺血和纤维化等均可能参与发病机制。因此,IPAH病 的具体病因尚未得到彻底阐明,IPAH临床指标的变化和潜在的相关机制仍需要 探索,以便使用低成本和安全的方法找到准确和具体的诊断标志物,从而改善患 者的预后。
近年来,随着脂质组学技术的逐渐成熟和完善,脂质代谢得到了广泛的研究。 对脂质代谢途径和代谢网络的广泛研究表明,脂质水平的变化可以反映几种酶水 平、活性和/或基因表达模式的变化。脂类是生物体内广泛分布的重要生物分子, 它们具有多样的结构,因此在各种生物过程中具有多种重要功能。它们不仅是细 胞和细胞器的重要组成部分,还参与细胞的能量转换、物质转运、信息识别、信 号传递、细胞生长、分化和凋亡。因此,脂质代谢及其功能变化对生物体内细胞 的生理功能和病理性疾病有着至关重要的影响。脂质代谢异常通常与代谢疾病、 心血管疾病和肿瘤密切相关。IPAH中也可能发生脂质代谢失调,例如甘油三酯 和HDL异常升高,这往往表明炎症的发生。
游离脂肪酸(FFAs)是脂类代谢的中间产物,是体内细胞能量代谢的重要 代谢底物,为机体的代谢提供能量。基础研究证明,部分脂质如FFAs对心血管 系统有积极的保护作用,其中二十二碳六烯酸(DHA)通过钾通道介导的肺动 脉超极化可导致肺动脉快速扩张,理论上对肺动脉高压患者的症状有一定的缓解 作用。然而,目前没有评估患者血浆中二十二碳六烯酸的表达对IPAH患者疾病 进展及预后的潜在影响。
发明内容
为了克服现有技术中的缺陷,本发明提供了一种特发性肺动脉高压的预后标 记物及其应用。
为实现上述目的,本发明采用如下技术方案:
本发明的第一方面是提供一种特发性肺动脉高压的预后标记物,其为DHA。
本发明的第二方面是提供DHA作为预后标记物在制备IPAH预后预测试剂 盒中的应用。
进一步地,上述IPAH预后预测包括患者生存期预测,较低水平的DHA预 示着IPAH病患者生存预后不良。
进一步地,上述试剂盒包括检测DHA水平的试剂。
进一步地,检测的DHA水平为待检测者血浆中的DHA水平。
本发明的第三方面是提供DHA在制备改善IPAH预后的药物中的应用,该 药物的有效成分为DHA。
本发明的第四方面是提供DHA在制备治疗IPAH的药物中的应用,该药物 的有效成分包括DHA。
进一步地,该药物还包括药学上可接受的载体或者赋形剂。
进一步地,该药物的剂型为滴剂、片剂、胶囊剂、口服液、口含剂、颗粒剂 或冲剂。
本发明采用以上技术方案,与现有技术相比,具有如下技术效果:
本发明首次发现游离脂肪酸水平与疾病严重程度相关,特别地发现较低水平 的DHA预示着IPAH病患者存活率低,为制备IPAH预后预测试剂盒、改善IPAH 预后的药物以及治疗IPAH的药物提供了策略。
附图说明
图1是本发明一实施例中每个样品中的血浆脂质的分析结果以及游离脂肪 酸数量的统计图;其中,图A显示了通过主成分分析每个样品的血浆脂质的结 果;图B显示了通过蛋白质谱分析每个样品的血浆脂质的结果;图C显示了游 离脂肪酸数量、种类及总数量统计图;其中,“FFA”表示为游离脂肪酸。“*” 表示P<0.05;“**”表示P<0.01;“ns”表示P≥0.05;
图2是本发明一实施例中IPAH患者不同风险组间FFAs水平比较;其中, 图A显示了不同风险组FFAs表达水平的比较结果;图B显示了存活患者和死亡 患者FFAs表达水平的比较结果;图C显示了男性和女性患者FFAs表达水平的 比较结果;其中,“FFA”表示为游离脂肪酸;“*”表示P<0.05;“**”表示P<0.01; “ns”表示P≥0.05;
图3显示了本发明一实施例中IPAH患者血脂显著差异与基线特征之间的关 系;其中,“*”表示P<0.05;“**”表示P<0.01;“ns”表示没有意义;
图4为本发明一实施例中IPAH单变量和多变量COX回归分析的森林图; 其中,“HR”表示为危害比,“CI”表示为置信区间;
图5为本发明一实施例中IPAH患者DHA受试者工作曲线分析结果;
图6为本发明一实施例中高DHA组和低DHA组IPAH患者的预测生存曲线 结果。
具体实施方式
本发明提供了特发性肺动脉高压的预后标记物及其应用,该预后标记为 DHA(二十二碳六烯酸),血浆中DHA的水平与IPAH患者预后成正相关,为制 备IPAH预后预测试剂盒提供了方向;同时,DHA可作为治疗IPAH的潜在选择。
下面通过具体实施例和附图对本发明进行详细和具体的介绍,以使更好的理 解本发明,但是下述实施例并不限制本发明范围。
实施例中方法如无特殊说明的采用常规方法,使用的试剂如无特殊说明的使 用常规市售试剂或按常规方法配制的试剂。
研究目标
以下实施例以2013年5月至2019年4月期间在上海市肺科医院接受治疗的 69例IPAH患者进行研究。根据欧洲心脏病学会(ESC)指南,IPAH的诊断定 义为通过右心导管术(RHC)测定:mPAP≥25mm Hg,肺毛细血管楔压(PCWP) ≤15mm Hg,PVR>3Wood units。与结缔组织病、先天性心脏病、门静脉高压症、 肺部疾病、慢性血栓栓塞症、左心疾病或厌食症相关的患者被排除在外。患有可 能影响激素代谢的急性或慢性疾病的患者,包括急性或慢性感染、慢性自身免疫 性疾病和既往明确的原发性内分泌疾病,以及正在接受或以前接受过激素(甲状 腺激素、合成类固醇或皮质类固醇)治疗或正在使用显著抑制激素生成的药物的 患者也被排除在外。
收集这69例IPAH患者的临床数据:人口统计学信息、世界卫生组织功能分 级(WHOFC)、6分钟步行距离(6MWD)、N末端脑钠肽前体(NT-proBNP)、 血流动力学参数,包括平均右心房压(mRAP)、平均肺动脉压(mPAP)、平均 肺动脉楔压(mPAWP)、PVR、心脏指数(CI)、混合静脉氧饱和度(SvO2)、其 他实验室参数和治疗方案。患者的风险水平根据以下六个指标来确定:WHO FC、 6MWD、mRAP、CI、SvO2和NT-proBNP。全因死亡率是从IPAH患者的确诊日期 到2020年12月估算的。
表1显示了研究参与患者在基线时的临床特征、血流动力学实验室结果和特 定治疗方案。69例IPAH患者的平均年龄为33.3±12.0岁;80.3%的患者为女性; 38名患者(62.3%)为WHO III/IV组。根据ESC指南,将69例IPAH患者分为 3组进行后续统计分析,分别将28、25和16例患者分为低危、中危和高危患者。 在平均69[8-92]个月的随访期间,8名患者(11.59%)死亡。
在年龄、mPAP或mPAWP方面,不同组之间没有发现显著差异。然而,在性 别、WHOFC、6MWD、NT-proBNP、mRAP、PVR、CI和SvO2方面存在显著差 异。本研究中的患者接受的治疗包括靶向药物,其包括5型磷酸二酯酶抑制剂(西 地那非、他达拉非和伐地那非)、口服内皮受体拮抗剂(安立生坦和波生坦)和 可溶性鸟苷酸环化酶刺激剂(利奥西呱),以及联合治疗和非特异性治疗药物。 不同风险组之间在药物使用方面没有明显差异。
表1参与患者人群的特征
通用方法
1.样本处理
将每个血浆样品(50μL)放入玻璃管中,并加入含有50μL内标(皮质酮-d8, 10μg/mL)的750μL甲醇中。涡旋2分钟后,将2.5mL二氯甲烷(DCM)加入混 合物中,再涡旋10分钟。然后加入625μL去离子水,再次涡旋,3,000rpm离心 15分钟,使混合物分离成不同的液相分层。收集下层并转移到新的玻璃管中。 上层用2mLDCM二次萃取。最后,合并有机层并蒸发至干。将干燥的提取物在 200μL醋酸铵:H2O(1:1,V/V)中复溶,用于LC-MS/MS分析。质量控制(QC)样 品通过混合等体积的所有样品制备,并遵循相同的制备程序。
2.LC-MS/MS分析
使用Triple QuadTM6500质谱仪(AB SCIEX,美国)和ExionLC液相色谱系 统(ABSCIEX,美国)通过亲水相互作用色谱-高效液相色谱和串联质谱 (HILIC-HPLC-MS/MS)分析上清液。对于液相色谱分离,使用了BEH酰胺亲水 色谱柱(100mm×2.1mm i.d.,1.7μm;Waters)。进样5μL样品并使用16分钟梯 度进行分离。柱流速维持在500μL/min,柱温40。℃
分别在正离子模式和负离子模式下获得电喷雾电离质谱。使用多反应监测 (MRM)模式收集目标脂质的转变信息。对于正模式和负模式,离子喷雾电压 分别设置为5500V和4500V;去簇电压(DP)设置为80V;加热毛细管温度保 持在550℃。气帘气、雾化器和加热器气体分别设置为35、55和55a.u.。
3.数据分析
对于连续变量,数据表示为具有标准偏差的平均值或具有四分位范围的中间 值;对于分类变量,数据表示为数字和百分比。按照95%置信区间计算风险比。 统计软件IBMSPSS Statistics(IBM,USA)24用于分析所有数据,包括临床参数 和所有患者的脂质分子的相对数量。根据《欧洲疾病指南》中规定的分类标准, 将患者分为低风险、中风险和高风险组,以评估已建立的分类指数参数和脂质分 子(IPAH潜在的生物标志物)之间的关系。
实施例1
本实施例对上述不同的IPAH患者的游离脂肪酸进行检测和比较,具体的操 作步骤和结果如下:
使用MultiQuan(SciexTM)软件对原始样品质量光谱数据进行峰提取、峰匹配、 峰对齐和归一化。基于自建脂质标准谱库,通过提取信噪比>3的脂质物质生成 鉴别列表,以内标物质为基础对峰面积进行归一化处理。在这个检测过程中,使 用无监督主成分分析(PCA)来观察样本之间的总体分布和组之间的分散度(图 1A);然后使用监督正交偏最小二乘判别分析(OPLS-DA)来区分各组之间代谢 谱的总体差异,并寻找各组之间不同的代谢物(图1B)。24个游离脂肪酸分子 的响应强度被认为是有效的(图1C)。
单因素方差分析用于检测不同风险组之间游离脂肪酸的相对数量是否有显 著差异,结果如表2所示。FFA(20:4)、FFA(20:5)、FFA(22:5)、FFA(22:6)、FFA (24:0)、FFA(30:4)表达差异显著,与FFA亚类变化趋势一致,低风险组水平显著 高于中高风险组。如图2A所示,游离脂肪酸(22:6),即二十二碳六烯酸(DHA), 显示了低风险组和高风险组之间最显著的差异。此外,低风险组的二十二碳六烯 酸水平高于中等风险组。存活患者的二十二碳六烯酸水平高于死亡患者(图2B)。IPAH患者的FFA(20:4)、FFA(20:5)、FFA(22:5)、DHA、FFA(24:0)或FFA(30:4) 水平没有显著的性别差异(图2C)。
表2 IPAH患者不同危险组间游离脂肪酸水平的比较
FFA | 低风险(n=31) | 中风险(n=21) | 高风险(n=17) | p值 |
FFA(14:0) | 73.8±7.3 | 72.1±6.2 | 69.5±8.3 | 0.157 |
FFA(14:1) | 58.5±5.7 | 58.3±5.1 | 56.0±4.6 | 0.259 |
FFA(16:0) | 92.5±5.6 | 91.3±4.4 | 92.4±5.6 | 0.681 |
FFA(16:1) | 75.8±6.2 | 75.3±5.9 | 74.5±5.1 | 0.757 |
FFA(16:2) | 62.1±4.3 | 61.4±3.1 | 59.1±3.3 | 0.032 |
FFA(18:1) | 108.5±4.4 | 107.1±2.9 | 107.3±3.8 | 0.377 |
FFA(18:2) | 109.1±4.6 | 107.9±3.2 | 107.5±3.9 | 0.405 |
FFA(18:3) | 86.8±5.4 | 85.4±5.2 | 84.3±5.4 | 0.288 |
FFA(20:1) | 64.8±5.6 | 63.6±4.2 | 62.4±4.2 | 0.249 |
FFA(20:2) | 72.1±9.8 | 68.4±7.1 | 66.7±6.6 | 0.078 |
FFA(20:3) | 76.8±5.2 | 75.9±4.0 | 73.9±5.2 | 0.157 |
FFA(20:4) | 86.5±6.2 | 84.1±4.1 | 81.5±6.2 | 0.017 |
FFA(20:5) | 73.0±4.2 | 69.5±3.7 | 68.6±3.5 | <0.001 |
FFA(22:0) | 73.9±8.6 | 74.2±10.2 | 67.9±6.1 | 0.051 |
FFA(22:1) | 73.3±4.8 | 72.5±2.6 | 71.0±4.0 | 0.168 |
FFA(22:2) | 72.0±4.3 | 70.8±3.3 | 70.5±3.4 | 0.306 |
FFA(22:3) | 82.5±4.4 | 82.2±2.3 | 80.9±3.8 | 0.357 |
FFA(22:4) | 67.6±5.5 | 66.8±3.7 | 64.8±4.3 | 0.153 |
FFA(22:5) | 77.9±6.4 | 75.5±5.5 | 72.5±5.8 | 0.013 |
FFA(22:6) | 88.3±4.9 | 83±4.7 | 81.6±4.8 | <0.001 |
FFA(24:0) | 78.7±5.5 | 75.4±3.8 | 73.5±6.2 | 0.005 |
FFA(24:1) | 64.7±4.2 | 64.1±2.7 | 62.4±3.5 | 0.115 |
FFA(30:2) | 72.1±4.5 | 70.7±3.3 | 69.5±4.6 | 0.112 |
FFA(30:4) | 88.5±4.1 | 85.8±3.9 | 85.8±4.6 | 0.033 |
注:表格中的数据以平均±标准偏差的形式显示。FFA(A:B)中A是分子中的碳原子数,B是分子中不饱和 键的数目。
实施例2
本实施例对IPAH病患者中的游离脂肪酸与临床参数的相关性进行研究,具 体的操作步骤和结果如下:
Spearman相关性分析是在患者的几个游离脂肪酸和基线临床参数之间进行 的,包括WHO-FC、NT-proBNP、mRAP、mPAP、mPAWP、CI、SvO2和PVR, 获得的结果如图3所示。FFA(20:4)、FFA(20:5)、FFA(22:5)、DHA、FFA(24:0)、 FFA(30:4)与上述临床参数显著相关。特别是,6种游离脂肪酸均与NT-proBNP 呈显著负相关,与心脏指数正相关。WHO-FC与FFA(20:5)、FFA(22:5)、DHA、 FFA(24:0)和FFA(30:4)呈显著负相关。PVR与FFA(20:4)、FFA(20:5)、FFA(22:5)、 DHA和FFA(24:0)呈显著负相关。同时,mRAP与FFA(20:4)、FFA(20:5)、FFA(22:5) 和DHA呈显著负相关。然而,mPAWP与6种游离脂肪酸均没有显著的相关性。 此外,DHA与WHO-FC、mPAP、PVR和NT-proBNP呈显著负相关,与6MWD 和CI呈显著正相关。
实施例3
本实施例对IPAH患者游离脂肪酸进行Cox回归分析,具体的操作步骤和结 果如下:
为了进一步探讨上述因素对患者生存率的影响,我们进行了单变量和多变量 Cox回归分析,结果如图4所示。
在单变量分析中,包括高密度脂蛋白(HDL)、总胆红素(TBIL)、肌酐(CR)、 游离脂肪酸(20:5)和DHA等在内的参数被确定为IPAH患者生存率的预测因子。 随后的多变量分析表明,DHA与IPAH患者的死亡率显著且独立相关。
实施例4
本实施例对筛选的可预测IPAH风险的脂质分子进行ROC分析Kaplan-Meier 生存曲线分析,具体的操作步骤和结果如下:
采用ROC分析以确定DHA作为IPAH患者死亡率预测因子的敏感性和特异 性,结果如图5所示,DHA曲线下面积(AUC)为0.845,界值为77.55,预测 IPAH生存率的灵敏度为0.967,特异性为0.625。根据DHA的界值,将患者分 为高DHA组和低DHA组。Kaplan-Meier曲线分析显示,高DHA水平的患者比 低二DHA水平的患者存活率更高(图6)。
由上述结果可知,较低水平的DHA预示着IPAH患者存活率低,血浆DHA 水平降低可能促进IPAH的发展,因DHA是一种有效的血管扩张剂,可迅速降 低肺动脉高压患者升高的肺血管阻力和压力,所以DHA可能是治疗IPAH的潜 在选择,直接或间接补充DHA可以减缓IPAH患者肺动脉重构的进程。
以上对本发明的具体实施例进行了详细描述,但其只作为范例,本发明并不 限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行等 同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明精神和范围下所 作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (9)
1.一种特发性肺动脉高压的预后标记物,其特征在于,为DHA。
2.DHA作为预后标记物在制备IPAH预后预测试剂盒中的应用。
3.根据权利要求2所述的应用,其特征在于,所述IPAH预后预测包括患者生存期预测,较低水平的DHA预示着IPAH患者生存预后不良。
4.根据权利要求2所述的应用,其特征在于,所述试剂盒包括检测DHA水平的试剂。
5.根据权利要求4所述的应用,其特征在于,所述检测的DHA水平为待检测者血浆中的DHA水平。
6.DHA在制备改善IPAH预后的药物中的应用,其特征在于,所述药物的有效成分为DHA。
7.DHA在制备治疗IPAH的药物中的应用,其特征在于,所述药物药物的有效成分包括DHA。
8.根据权利要求6或7所述的应用,其特征在于,所述药物还包括药学上可接受的载体或者赋形剂。
9.根据权利要求6或7所述的应用,其特征在于,所述药物的剂型为滴剂、片剂、胶囊剂、口服液、口含剂、颗粒剂或冲剂。
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CN115166100A (zh) * | 2022-08-03 | 2022-10-11 | 上海市肺科医院 | 检测ffa和/或mag的试剂在制备预测ipah发病风险的产品中的应用 |
WO2024065892A1 (zh) * | 2022-09-26 | 2024-04-04 | 中国医学科学院基础医学研究所 | 检测嗜酸性粒细胞的试剂、嗜酸性粒细胞及其胞质内容物和羟基二十二碳六烯酸的应用 |
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