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Article(id=1146098732887544626, tenantId=1146029695717560320, journalId=1146031591421210625, issueId=1146500022360707816, articleNumber=null, orderNo=23, doi=10.3981/j.issn.1000-7857.2024.12.01772, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1734364800000, receivedDateStr=2024-12-17, revisedDate=1737475200000, revisedDateStr=2025-01-22, acceptedDate=1744214400000, acceptedDateStr=2025-04-10, onlineDate=1751180831403, onlineDateStr=2025-06-29, pubDate=1745769600000, pubDateStr=2025-04-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1749052800000, onlineIssueDateStr=2025-06-05, onlineJustAcceptDate=1751285400626, onlineJustAcceptDateStr=2025-06-30, onlineFirstDate=1751180831403, onlineFirstDateStr=2025-06-29, sourceXml=null, magXml=null, createTime=1751180831403, creator=18627231156, updateTime=1774079636052, updator=sys-migrate, issue=Issue{id=1146500022360707816, tenantId=1146029695717560320, journalId=1146031591421210625, year='2025', volume='43', issue='8', pageStart='1', pageEnd='112', issueExtLink='null', onlineDate='null', pubDate='1745769600000', pubDateStr='2025-04-28', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1751276506271, creator='13701087609', updateTime=1774330523255, updator='13041195026', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1243195578088276195, tenantId=1146029695717560320, journalId=1146031591421210625, issueId=1146500022360707816, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1243195578088276196, tenantId=1146029695717560320, journalId=1146031591421210625, issueId=1146500022360707816, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=80, endPage=87, ext={EN=ArticleExt(id=1146098733369889636, articleId=1146098732887544626, tenantId=1146029695717560320, journalId=1146031591421210625, language=EN, title=Application of echocardiography in the assessment of right heart structure and function in rats with pulmonary hypertension, columnId=1150494644690366681, journalTitle=Science & Technology Review, columnName=Papers, runingTitle=null, highlight=null, articleAbstract=

To establish a stable and reliable non−invasive method for evaluating the right heart structure and function in rats with pulmonary hypertension (PH) using small animal echocardiography. Male SD rats were randomly divided into a control group and a model group. The model group was injected subcutaneously with the vascular endothelial growth factor receptor inhibitor SU5416 (20 mg/kg body weight) in the neck and placed in a hypoxia chamber with 10% oxygen concentration for 3 weeks, then transferred to a normoxia environment for another 3 weeks to construct a severe PH rat model. The control group was raised in a normal environment. Six weeks after modeling, animals were anesthetized, and echocardiographic measurements and right heart catheterization were performed to collect relevant hemodynamic indices. Echocardiographic indices of the rat hearts were analyzed for uniformity and retest reliability, correlated with the right ventricular systolic pressure measured by right heart catheterization, and their diagnostic value for PH rats was evaluated. The right heart structure and function evaluation indices established in PH rats using small animal echocardiography showed good uniformity and retest reliability. The end−diastolic right ventricular free wall thickness, end−systolic right ventricular free wall thickness, tricuspid annular plane systolic excursion, and pulmonary artery flow acceleration time/ejection time and pulmonary artery flow acceleration time were significantly correlated with the right ventricular systolic pressure measured by right heart catheterization (P<0.001) and had high diagnostic value. Small animal echocardiography provides a non−invasive, stable, and reproducible method for evaluating the right heart structure and function in PH rats, which can be used to assess the severity of the disease in PH rat models.

, authors=null, authorsList=Yuqin CHEN, Yuanhui XIONG, Meidan KUANG, Jian WANG, authorCompany=null, correspAuthors=Jian WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=All rights reserved. Unauthorized reproduction is prohibited., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1146098734619792363, articleId=1146098732887544626, tenantId=1146029695717560320, journalId=1146031591421210625, language=CN, title=超声心动图在重度肺动脉高压大鼠右心结构与功能评估中的应用, columnId=1146540929516700224, journalTitle=科技导报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

利用小动物超声建立稳定、可靠的无创评价肺动脉高压大鼠右心结构和功能评价的方法，将雄性SD大鼠随机分为对照组和模型组，模型组采用颈部皮下注射血管内皮细胞生长因子受体抑制剂SU5416（20 mg/kg体重）后置于10%氧浓度低氧箱中饲养3周后转至常氧环境饲养3周，构建重度肺动脉高压大鼠模型。对照组置于正常环境进行饲养。造模6周后对动物进行麻醉后，进行心脏超声测量及右心导管术进行血流动力学相关指标采集，并对大鼠心脏超声指标进行均一性和重测信度分析，与大鼠右心室收缩压进行相关性分析，评价其对肺动脉高压大鼠的诊断价值。结果发现通过小动物心脏超声建立的肺动脉高压大鼠右心结构与功能评价指标具有较好的均一性及重测信度。舒张末期右室游离壁厚度、收缩末期右室游离壁厚度、三尖瓣环收缩期位移、肺动脉血流加速时间/射血时间和肺动脉血流加速时间与右心导管测得右心室收缩压具有较好的相关性（P < 0.001）及较高的诊断价值。因此，小动物超声是一种无创、稳定、重复性良好的肺动脉高压大鼠右心结构和功能评价方法，可用于该模型疾病严重程度的评估。

, authors=

陈豫钦，副研究员，研究方向为肺动脉高压发病机制与药物研发，电子信箱:

熊缘慧（共同第一作者），硕士研究生，研究方向为肺动脉高压发病机制，电子信箱:

, authorsList=陈豫钦, 熊缘慧, 邝美丹, 王健, authorCompany=null, correspAuthors=王健, authorNote=null, correspAuthorsNote=
王健（通信作者），教授，研究方向为肺动脉高压发病机制，电子信箱:
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陈豫钦，副研究员，研究方向为肺动脉高压发病机制与药物研发，电子信箱:

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陈豫钦，副研究员，研究方向为肺动脉高压发病机制与药物研发，电子信箱:

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熊缘慧（共同第一作者），硕士研究生，研究方向为肺动脉高压发病机制，电子信箱:

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熊缘慧（共同第一作者），硕士研究生，研究方向为肺动脉高压发病机制，电子信箱:

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Archives of Cardiovascular Diseases, 2014, 107 (10): 529- 539., articleTitle=Echocardiographic assessment of right ventricular systolic function in a population of unselected patients before cardiac surgery: A multiparametric approach is necessary, refAbstract=null)], funds=[Fund(id=1242143296621978060, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, awardId=82170069, language=CN, fundingSource=国家自然科学基金面上项目(82170069), fundOrder=null, country=null), Fund(id=1242143296701669837, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, awardId=2024A1515011208, language=CN, fundingSource=广东省基础与应用基础研究基金自然科学基金面上项目(2024A1515011208), fundOrder=null, country=null), Fund(id=1242143296764584399, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, awardId=2025A03J4478, language=CN, fundingSource=广州市科技计划项目2025年度市校（院）企联合资助项目(2025A03J4478), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1242143292721275295, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, xref=null, ext=[AuthorCompanyExt(id=1242143292729663904, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, companyId=1242143292721275295, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China), AuthorCompanyExt(id=1242143292742246817, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, companyId=1242143292721275295, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=呼吸疾病全国重点实验室, 广州呼吸健康研究院, 广州医科大学附属第一医院/国家呼吸医学中心, 广州 510120)])], figs=[ArticleFig(id=1242143295753757120, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=EN, label=null, caption=null, figureFileSmall=Vj53uaHegovbc1Fu1i713A==, figureFileBig=HTcfXptIoGB3DiGC4RUkLg==, tableContent=null), ArticleFig(id=1242143295829254595, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=CN, label=图1, caption=评价右心结构与功能的彩超指标与测量方法

（a）B-mode下彩超图像，图中所示分别为右心室（RV）、室间隔（IVS）、左心室（LV）、右心房（RA）和左心房（LA），箭头所指部位三尖瓣环；（b）B-mode下彩超图像，白色线条所圈区域为右心室面积；（c）为三尖瓣环在M-mode下的彩超图像，绿色线条为TAPSE；（d）B-mode下彩超图像，图中所示分别为右心室（RV）、室间隔（IVS）、左心室（LV）、右心室流出道（RVOT）和主动脉（aorta），箭头所指部位为右室游离壁；（e）经左心室乳头肌M-mode下彩超图像；（f）为（e）图的放大图像，红色线条为舒张末期右心室内径，蓝色线条为收缩末期右室内径，黄色线条为舒张末期右室游离壁厚度，白色线条为收缩末期右室游离壁厚度；（g）在肺动脉瓣口所测得的血流速度与时间关系的波形；（h）为（g）图的放大图像，蓝色线为PAT（从肺动脉血流速度从零开始加速到最大速度的时间），红色线条表示PET（整个射血时间）

, figureFileSmall=Vj53uaHegovbc1Fu1i713A==, figureFileBig=HTcfXptIoGB3DiGC4RUkLg==, tableContent=null), ArticleFig(id=1242143296022192580, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=EN, label=null, caption=null, figureFileSmall=2UOqV9wPU2O1Try3N+aDFg==, figureFileBig=nKXQ5gEQOgKfjh2FdNGZhQ==, tableContent=null), ArticleFig(id=1242143296093495749, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=CN, label=图2, caption=各项彩超指标的ROC曲线, figureFileSmall=2UOqV9wPU2O1Try3N+aDFg==, figureFileBig=nKXQ5gEQOgKfjh2FdNGZhQ==, tableContent=null), ArticleFig(id=1242143296160604614, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
大鼠数目 mean±SD 变异系数/% 差异均值/% 组内相关系数（p）
舒张末期右室游离壁厚度 27 0.51±0.05 10.9 4.2±3.4 0.894（p＜0.001）
收缩末期右室游离壁厚度 27 1.04±0.20 14.0 7.4±7.9 0.894（p＜0.001）
右心室舒张末期直径 28 2.11±0.54 21.2 7.3±7.8 0.894（p＜0.001）
右室收缩末期内径 28 1.37±0.47 15.8 4.4±2.9 0.894（p＜0.001）
右室游离壁缩短分数 27 0.55±0.11 16.7 8.6±6.9 0.894（p＜0.001）
右室内径缩短分数 28 0.45±0.10 28.3 10.6±10.4 0.894（p＜0.001）
三尖瓣环收缩期位移 23 3.74±0.56 10.6 5.8±4.6 0.894（p＜0.001）
肺动脉血流加速时间/射血时间 33 0.41±0.05 13.1 2.1±2.1 0.894（p＜0.001）
肺动脉血流加速时间 33 32.20±5.06 13.3 1.6±1.1 0.894（p＜0.001）
室面积变化分数 20 46.10±4.05 11.7 7.3±3.2 0.894（p＜0.001）
), ArticleFig(id=1242143296223519175, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=CN, label=表1, caption=

各项超声指标的均一性及在观察者内的变异性

, figureFileSmall=null, figureFileBig=null, tableContent=
大鼠数目 mean±SD 变异系数/% 差异均值/% 组内相关系数（p）
舒张末期右室游离壁厚度 27 0.51±0.05 10.9 4.2±3.4 0.894（p＜0.001）
收缩末期右室游离壁厚度 27 1.04±0.20 14.0 7.4±7.9 0.894（p＜0.001）
右心室舒张末期直径 28 2.11±0.54 21.2 7.3±7.8 0.894（p＜0.001）
右室收缩末期内径 28 1.37±0.47 15.8 4.4±2.9 0.894（p＜0.001）
右室游离壁缩短分数 27 0.55±0.11 16.7 8.6±6.9 0.894（p＜0.001）
右室内径缩短分数 28 0.45±0.10 28.3 10.6±10.4 0.894（p＜0.001）
三尖瓣环收缩期位移 23 3.74±0.56 10.6 5.8±4.6 0.894（p＜0.001）
肺动脉血流加速时间/射血时间 33 0.41±0.05 13.1 2.1±2.1 0.894（p＜0.001）
肺动脉血流加速时间 33 32.20±5.06 13.3 1.6±1.1 0.894（p＜0.001）
室面积变化分数 20 46.10±4.05 11.7 7.3±3.2 0.894（p＜0.001）
), ArticleFig(id=1242143296286433736, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
大鼠数目 r 相关性检验p值 调整R2 回归方程
舒张末期右室游离壁厚度 39 0.842 ＜0.001 0.719 y=0.026x−0.238
收缩末期右室游离壁厚度 39 0.809 ＜0.001 0.652 y=0.028x+0.331
右心室舒张末期直径 41 0.491 ＜0.001 0.262
右室收缩末期内径 41 0.562 ＜0.001 0.354
右室游离壁缩短分数 39 −0.565 ＜0.001 0.345
右室内径缩短分数 40 −0.601 ＜0.001 0.424
三尖瓣环收缩期位移 33 −0.772 ＜0.001 0.493
肺动脉血流加速时间/射血时间 43 −0.820 ＜0.001 0.615 y=−0.006x+0.567
肺动脉血流加速时间 43 −0.768 ＜0.001 0.498 y=−0.385x+40.525
室面积变化分数 10 −0.539 ＜0.001 0.201
), ArticleFig(id=1242143296361931209, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=CN, label=表2, caption=

各项超声指标与右心室收缩压相关性分析

, figureFileSmall=null, figureFileBig=null, tableContent=
大鼠数目 r 相关性检验p值 调整R2 回归方程
舒张末期右室游离壁厚度 39 0.842 ＜0.001 0.719 y=0.026x−0.238
收缩末期右室游离壁厚度 39 0.809 ＜0.001 0.652 y=0.028x+0.331
右心室舒张末期直径 41 0.491 ＜0.001 0.262
右室收缩末期内径 41 0.562 ＜0.001 0.354
右室游离壁缩短分数 39 −0.565 ＜0.001 0.345
右室内径缩短分数 40 −0.601 ＜0.001 0.424
三尖瓣环收缩期位移 33 −0.772 ＜0.001 0.493
肺动脉血流加速时间/射血时间 43 −0.820 ＜0.001 0.615 y=−0.006x+0.567
肺动脉血流加速时间 43 −0.768 ＜0.001 0.498 y=−0.385x+40.525
室面积变化分数 10 −0.539 ＜0.001 0.201
), ArticleFig(id=1242143296437428682, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
收缩末期右室游离壁厚度 收缩末期右室游离壁厚度 肺血流加速时间/肺射血时间 肺血流加速时间 三尖瓣环位移
ROC曲线下面积 0.969 0.918 0.946 0.912 0.958
约登指数 0.918 0.692 0.765 0.737 0.810
关联准则 >0.615 >1.21 ≤0.346 ≤26.4 ≤2.91
敏感性/% 96.2 86.5 94.2 80.4 84.1
特异性/% 95.7 82.6 82.2 93.3 96.9
阴性预测值/% 95.6 84.4 92.7 80.0 81.6
阳性预测值/% 94.3 84.9 84.5 93.0 97.4
准确率/% 94.9 84.7 87.9 85.7 89.5
大鼠数目 98 98 97 96 76
), ArticleFig(id=1242143296500343243, tenantId=1146029695717560320, journalId=1146031591421210625, articleId=1146098732887544626, language=CN, label=表3, caption=

超声心动图参数检测肺动脉高压的诊断价值

, figureFileSmall=null, figureFileBig=null, tableContent=
收缩末期右室游离壁厚度 收缩末期右室游离壁厚度 肺血流加速时间/肺射血时间 肺血流加速时间 三尖瓣环位移
ROC曲线下面积 0.969 0.918 0.946 0.912 0.958
约登指数 0.918 0.692 0.765 0.737 0.810
关联准则 >0.615 >1.21 ≤0.346 ≤26.4 ≤2.91
敏感性/% 96.2 86.5 94.2 80.4 84.1
特异性/% 95.7 82.6 82.2 93.3 96.9
阴性预测值/% 95.6 84.4 92.7 80.0 81.6
阳性预测值/% 94.3 84.9 84.5 93.0 97.4
准确率/% 94.9 84.7 87.9 85.7 89.5
大鼠数目 98 98 97 96 76
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超声心动图在重度肺动脉高压大鼠右心结构与功能评估中的应用
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陈豫钦 , 熊缘慧 , 邝美丹 , 王健 *
科技导报 | 研究论文 2025,43(8): 80-87
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科技导报 |研究论文 2025 , 43 (8) : 80 -87
超声心动图在重度肺动脉高压大鼠右心结构与功能评估中的应用
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广州医科大学附属第一医院/国家呼吸医学中心, 广州 510120)])])]
陈豫钦 , 熊缘慧 , 邝美丹, 王健*
作者信息
  • 呼吸疾病全国重点实验室, 广州呼吸健康研究院, 广州医科大学附属第一医院/国家呼吸医学中心, 广州 510120
通讯作者:
王健（通信作者），教授，研究方向为肺动脉高压发病机制，电子信箱:
Application of echocardiography in the assessment of right heart structure and function in rats with pulmonary hypertension
Yuqin CHEN , Yuanhui XIONG , Meidan KUANG, Jian WANG*
Affiliations
  • State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
出版时间: 2025-04-28 doi: 10.3981/j.issn.1000-7857.2024.12.01772
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摘要
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利用小动物超声建立稳定、可靠的无创评价肺动脉高压大鼠右心结构和功能评价的方法，将雄性SD大鼠随机分为对照组和模型组，模型组采用颈部皮下注射血管内皮细胞生长因子受体抑制剂SU5416（20 mg/kg体重）后置于10%氧浓度低氧箱中饲养3周后转至常氧环境饲养3周，构建重度肺动脉高压大鼠模型。对照组置于正常环境进行饲养。造模6周后对动物进行麻醉后，进行心脏超声测量及右心导管术进行血流动力学相关指标采集，并对大鼠心脏超声指标进行均一性和重测信度分析，与大鼠右心室收缩压进行相关性分析，评价其对肺动脉高压大鼠的诊断价值。结果发现通过小动物心脏超声建立的肺动脉高压大鼠右心结构与功能评价指标具有较好的均一性及重测信度。舒张末期右室游离壁厚度、收缩末期右室游离壁厚度、三尖瓣环收缩期位移、肺动脉血流加速时间/射血时间和肺动脉血流加速时间与右心导管测得右心室收缩压具有较好的相关性（P < 0.001）及较高的诊断价值。因此，小动物超声是一种无创、稳定、重复性良好的肺动脉高压大鼠右心结构和功能评价方法，可用于该模型疾病严重程度的评估。

超声心动图  /  肺动脉高压  /  右心功能

To establish a stable and reliable non−invasive method for evaluating the right heart structure and function in rats with pulmonary hypertension (PH) using small animal echocardiography. Male SD rats were randomly divided into a control group and a model group. The model group was injected subcutaneously with the vascular endothelial growth factor receptor inhibitor SU5416 (20 mg/kg body weight) in the neck and placed in a hypoxia chamber with 10% oxygen concentration for 3 weeks, then transferred to a normoxia environment for another 3 weeks to construct a severe PH rat model. The control group was raised in a normal environment. Six weeks after modeling, animals were anesthetized, and echocardiographic measurements and right heart catheterization were performed to collect relevant hemodynamic indices. Echocardiographic indices of the rat hearts were analyzed for uniformity and retest reliability, correlated with the right ventricular systolic pressure measured by right heart catheterization, and their diagnostic value for PH rats was evaluated. The right heart structure and function evaluation indices established in PH rats using small animal echocardiography showed good uniformity and retest reliability. The end−diastolic right ventricular free wall thickness, end−systolic right ventricular free wall thickness, tricuspid annular plane systolic excursion, and pulmonary artery flow acceleration time/ejection time and pulmonary artery flow acceleration time were significantly correlated with the right ventricular systolic pressure measured by right heart catheterization (P<0.001) and had high diagnostic value. Small animal echocardiography provides a non−invasive, stable, and reproducible method for evaluating the right heart structure and function in PH rats, which can be used to assess the severity of the disease in PH rat models.

echocardiogram  /  pulmonary hypertension  /  right ventricular function
陈豫钦, 熊缘慧, 邝美丹, 王健. 超声心动图在重度肺动脉高压大鼠右心结构与功能评估中的应用. 科技导报, 2025 , 43 (8) : 80 -87 . DOI: 10.3981/j.issn.1000-7857.2024.12.01772
Yuqin CHEN, Yuanhui XIONG, Meidan KUANG, Jian WANG. Application of echocardiography in the assessment of right heart structure and function in rats with pulmonary hypertension[J]. Science & Technology Review, 2025 , 43 (8) : 80 -87 . DOI: 10.3981/j.issn.1000-7857.2024.12.01772
正文
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肺动脉高压（pulmonary hypertension，PH）是一种致命的进行性疾病，可导致肺血管阻力和肺动脉压力的进行性升高，继而发展成右心衰竭甚至死亡[1]。据估算PH全球患病率约为1%，65岁以上人群患病率高达10%[2]，中国约有1200万名PH患者。近年来虽然PH的发病机制及药物研发方面取得一定的进展，但疾病的早期诊断及长期预后的改善这两大重要问题仍未解决，仍需进一步加强PH发病机制及药物研发基础研究。其中，PH动物模型的血流动力学及右心功能评价为PH基础研究及药物评价的核心指标，目前多采用右心导管或其他有创手术测得右心室压及肺动脉压。但该方法具有手术操作难度大、有创、不适用于多次动态评价等局限性，且无法对模型动物的右心功能进行评价。心脏彩超是临床上进行PH初筛、疾病严重程度及右心功能评价的重要手段[3-5]。对于PH基础研究，小动物心脏彩超对肺血流动力学和右心功能的评价同样重要。小动物超声具有无创、适时的优点，可连续多次进行模型动物评估。近年来虽有研究者对PH大鼠右心功能进行超声评价，但是测定方法各不相同，缺乏公认的标准[6-10]。本研究通过建立低氧联合注射Sugen致重度PH（Sugen hypoxia induced-pulmonary hypertension，SuHx-PH）大鼠模型，建立心脏彩超评估肺血流动力学及右心评估的方法，并与右心导管测得的右心室压进行相关性分析，确定最佳的无创评价指标。
1 材料与方法
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1.1 实验动物
成年无特定病原菌（specific pathogen free，SPF）级SD（Sprague-Dawley）大鼠，由广东省实验动物中心提供[许可证号：SCXK（粤）2013-0002]。饲养于呼吸疾病全国重点实验室SPF级动物房，自由饮食。所有动物处理操作规范均通过广州医科大学附属第一医院动物伦理委员会批准。
1.2 主要试剂与仪器
SU5416购于美国MCE公司，异氟烷购于深圳瑞沃德公司。Vevo®2100超声成像系统为加拿大Visual Sonics公司产品，小动物生理仪为澳大利亚ADI公司产品，小动物气体麻醉机为深圳瑞沃德产品。
1.3 SuHx-PH动物模型的制备
造模的第0天，予SD大鼠颈部皮下注射20 mg/kg血管内皮细胞生长因子受体（vascular endothelial growth factor receptor, VEGFR）抑制剂SU5416。随后将大鼠置于10% 氧浓度低氧箱中放置3周，再置于常氧下饲养3周。对照组大鼠注射同等剂量的抑制剂，饲养于常氧环境。于造模后第1、2、4、6周时分别进行小动物心脏超声测定及经颈静脉右心导管测定右心室压。
1.4 大鼠心脏彩超的测定及指标获取
用5% 的异氟烷对大鼠进行诱导麻醉后用2% 的浓度维持麻醉，固定于小动物超声仪加热板动物四肢固定装置，维持动物体温，根据测定层面，调节动物体位，使用超声系统（VisualSonics Vevo 2100）连接探头（MS-250，13~24 MHz）经过腹部皮肤进行超声测量。同一只大鼠进行2次测量，间隔5 min。记录影像用Vevo LAB 3.1.1软件进行测算和分析。
1）室面积变化分数（fractional area change，FAC）和三尖瓣环收缩期位移（tricuspid annular plane systolic excursion，TAPSE）：FAC用于评估右心室收缩功能。超声探头置于心尖短轴切面，将动物头部向下倾斜旋转，同时倾斜探头角度，探头臂朝向操作者，即获得大鼠心尖四腔心切面，通过B-mode图像下分别测量舒张末期与收缩末期右心室面积，FAC=（（舒张末面积-收缩末面积）/舒张末面积×100%）；TAPSE可反映右心室的纵向收缩功能，探头位置同前，在四腔室右心室为主层面的M-mode图像下测量三尖瓣环在收缩末期到舒张末期移动的纵向距离（图 1），测量至少5个心动周期，取平均值。
2）舒张末期右室游离壁厚度（right ventricular end-diastolic wall thickness，RVEDWT）、收缩末期右室游离壁厚度（right ventricular end-systolic wall thickness，RVESWT）、右心室舒张末期直径（right ventricular end-diastolic diameter，RVEDD）、右室收缩末期内径（right ventricular end-systolic diameter，RVESD）、右室游离壁缩短分数（right ventricular wall thickness fractional shortening，RVWTFT）、右室内径缩短分数（right ventricular diameter fractional shortening，RVDFS）：RVEDWT、RVESWT、RVEDD、RVESD能显示右心室在心动周期中室壁厚度和室腔大小，反映右心室的结构变化情况。RVWTFT、RVDFS可反映右心室的收缩功能。超声探头置于胸骨右侧，探头垂直放置，切迹朝向动物头部，逆时针旋转探头约45°，确定心脏长轴切面，该切面能显示右心室游离壁、右心室腔、右心室流出道、室间隔、左心室和主动脉，在平左心室乳头肌的位置通过M-mode模式测得，排除呼吸的影响，测量至少3个周期，取平均值。RVWTFT=（RVESWT-RVEDWT）/RVESWT；RVDFS=（RVEDD- RVESD）/RVEDD。
3）肺动脉血流加速时间/射血时间（pulmonary artery acceleration time/pulmonary ejection time，PAT/ PET）：PAT指肺动脉加速时间（从肺动脉起始处到肺动脉流速达到峰值的时间），PET指肺动脉射血时间（右心室射血到肺动脉时间，即肺动脉血流持续时间），这一比值的变化与肺动脉压的升高和右心功能的改变相关。在胸骨旁长轴切面，将探头稍转向动物左肩，即可看到肺动脉；在胸骨短轴旁基础上，将探头向大鼠头侧移动，将看到左室流出道出口，呈环形，围绕出口外的血管即肺动脉，同时可看到左右两个肺动脉分支。在靠近肺动脉瓣口的位置通过PW模式，利用脉冲多普勒可以测量肺动脉流出血流，计算至少5个肺血流周期，取平均数。
1.5 经颈静脉测定大鼠右心室压
用5% 的异氟烷对大鼠进行诱导麻醉后用2% 的浓度维持麻醉，放置在动物体温维持垫上，用酒精消毒动物右侧颈部毛皮，用眼科剪小心将颈部皮肤剪开，钝性分离筋膜和肌肉组织，找到并游离颈静脉，结扎远心端，用显微剪在近心端剪一约2 mm的小口，将压力导管从颈静脉插入右心室，出现稳定的右心室压力波形后，维持至少1 min，将导管拔出。计算稳定波形中至少30 s的平均右心室收缩压（right ventricular systolic pressure，RVSP）。
1.6 统计学分析
采用SPSS 16.0及Medcalc16.2统计软件进行统计分析，实验结果用均值±标准差（mean±SD）表示。观测者内变异性用变异系数（coefficient of variation，CV）、差值均值（mean difference，MD）及组内相关系数（intraclass correlation coefficient，ICC）来评价。ICC值用SPSS中Two-Way Mixed模型、consistency型、single measure的方法计算。若两连续性变量均满足正态分布，使用Pearson相关性分析。否则，使用Spearman相关性分析；如果两变量相关系数较高，并且标准化残差呈近似正态分布且通过Durbin-Watson检验呈独立性，使用线性回归。使用Medcalc16.2统计软件绘制ROC曲线，计算曲线下面积（area under the ROC curve，AUC）、特异性、敏感性、阳性预测值、阴性预测值和准确性。以P < 0.05为有统计学差异，P < 0.01为有显著统计学差异。
2 结果
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2.1 各项超声指标的均一性和重测信度
如表 1所示，除RVEDD和RVDFS外，其他指标（如RVEDWT、RVESWT、RVESD、RVWTFT、TAPSE、PAT/PET、PAT、FAC）的变异系数（CV）均小于20，具有良好的一致性；MD值大多小于10，除了RVDFS外，其余指标均符合要求。重测信度方面，除TAPSE和FAC外，其他指标的ICC值均大于0.8，显示出较好的可靠性。
2.2 各项超声指标与右心室收缩压的相关性
如表 2所示，RVEDWT、RVESWT、PAT/PET与RVSP之间存在高度相关性，相关性检验p值均 < 0.001，且r值分别为0.842、0.809和-0.820，均大于0.8，回归分析结果表明这些变量与RVSP的线性关系较好，调整后的R2分别为0.719、0.652和0.615，拟合优度较高。而PAT和TAPSE的相关性较强，r值分别为-0.768和-0.772，回归方程拟合优度较一般，R2分别为0.498和0.493。其他变量如RVEDD、RVESD、RVWTFT、RVDFS和FAC与RVSP的相关性较弱。
2.3 各项超声指标对肺动脉高压的诊断价值
如表 3、图 2所示，本实验通过RVSP区分大鼠是否罹患肺动脉高压。根据RVSP的ROC曲线分析，确定最佳临界值为34.81 mmHg。结果显示，RVEDWT、RVESWT、PAT/PET、PAT和TAPSE的AUC均大于0.9，诊断准确性较高。特别是RVEDWT，具有最高的诊断价值，其约登指数、敏感性、特异性和准确性均超过90%，其他指标如RVESWT、PAT/ PET、PAT及TAPSE的诊断性能也表现良好，均超过80%。
3 结果与讨论
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PH的诊断标准为成人静息状态下平均肺动脉压力（mean pulmonary artery pressure，mPAP）≥ 20 mmHg，通常通过右心导管术（right heart catheter，RHC）进行测定[11]。然而，RHC有创且操作复杂，限制了其在PH筛查和病情监测中的应用。心脏彩超作为一种无创、便捷的检查方法，广泛用于PH的初筛、严重程度评估及右心功能评价。临床上，肺动脉压力估算常通过三尖瓣反流速度、右心房大小和上腔静脉塌陷程度等指标[12]。对于小动物模型，尤其是大鼠，因探头尺寸和心脏位置等限制，三尖瓣反流难以用于评估肺动脉压力。右心室的功能评价需区别于左心室，主要通过TAPSE、FAC、Tei指数（心肌作动指数）等指标[13]。尽管大鼠右心功能的超声评价尚无统一标准，肺血流图谱（如PAT）已被证明与有创测定的肺动脉压力高度相关，且与PH的诊断及预后有较好关联[14-17]。
研究发现，PAT与mPAP具有显著的相关性，且通过PAT/PET标准化后，能更准确地评估PH的严重程度。PAT/PET和PAT分别在PH诊断中的准确性为87.9% 和85.7%，其中PAT/PET具有较高的敏感性，而PAT则具有较高的特异性。结合两者可提高诊断正确率（94.9%）。PAT时间越短，通常与肺动脉压力升高相关，反映右心负担增加，而右心室在较高的肺动脉压力下可能需要更长时间完成射血过程，PET可能会延长。因此，肺血流图谱，特别是PAT/PET，作为评估PH及其严重程度的重要工具，具有较高的临床价值。
右心室游离壁厚度是评价PH右心室结构改变的一个重要指标[18]，当肺动脉压力升高时，右心室通过心肌细胞肥大来增加收缩力以克服升高的后负荷，从而维持全身正常的血液循环。临床上测量右心室游离壁厚度的方法比较固定，主要测量RVEDWT，可在从肋下窗用M型或2D超声心动图测得[19]。在大鼠上，右室游离壁厚度也容易测得，但是缺乏统一标准，测量位置不固定，这也使观察者间结果差异增大。本研究探讨了右心室游离壁厚度（RVEDWT和RVESWT）在PH中作为评估右心室结构改变的指标。通过左心室乳头肌用M型超声心动图，能够清晰显示右心室的舒张和收缩动态，进而测量右心室游离壁的厚度。为进一步评估右心室的变化，创立了衍生指标RVWTFT（即右心室收缩时游离壁增厚程度的反映）。本研究发现，RVEDWT和RVESWT与RVSP具有较强相关性（相关系数r分别为0.842和0.809），且其诊断PH的准确性较高。RVEDWT的诊断正确率为95.6%，敏感性、特异性、预测值均超过90%，具有极高的诊断价值。RVESWT也具备一定的诊断价值，但相对较弱。尽管RVWTFT的相关性一般，但其重测信度良好。由于本次模型最长时间仅6周，此时右心室可能并没有进入失代偿期，更严重程度的PH的RVSP是否与右室游离壁厚度具有强相关性仍需进一步研究。另外，对于治疗有效的PH患者或动物，其肺动脉压力下降，但右心室的重构可能并不能快速恢复，因此，此相关性和线性回归仅适用于未经治疗、右心室未失代偿的PH。总之，RVEDWT和RVESWT可作为PH右心室结构改变的可靠指标，具有较高的临床诊断价值。
右心室内径是评估右心室结构的重要指标，临床上通常通过四腔室B型超声心动图测量[20]。然而，在大鼠模型中，缺乏统一的标准，研究者尝试使用不同视角（如长轴、短轴和四腔室）进行测量。本研究中的测量方法同右心室游离壁厚度，由于右心室呈星月型，无法像左心室那样在前后壁做M型超声心动图。因此，本研究选取在右心室游离壁和室间隔之间进行M型测量，由于室间隔的运动模式与心室壁不同，且受到心室容量和左右心室相互作用的影响，右心室的相关测量（如RVEDD、RVESD、RVDFS）存在一定的均一性差异，但具有较好的重测信度。RVEDD、RVESD和RVDFS虽然与PH相关性较弱，但在后续模型中，它们对PH的严重程度具有一定的提示作用，尤其是RVDFS的下降，可能与右心室的舒缩功能下降有关。TAPSE和FAC是临床上常用的右心舒张和收缩功能评价指标[21-22]。TAPSE通过四腔室M型超声心动图测量，FAC则通过B型超声心动图获得。本实验方法与临床类似，但由于小动物超声成像系统只能提供垂直M型图像，增加了TAPSE测量的难度，影响其重测信度。另外四腔室图像的选择和清晰度对FAC和TAPSE的准确性至关重要。因此本研究不推荐FAC和TAPSE单独用于PH大鼠右心功能评估。
综上所述，超声心动图作为一种无创、便捷的评估工具，在PH的诊断、病情监测及右心功能评估中具有显著优势。通过综合分析右心室游离壁厚度、肺血流图谱及右心室内径等多项指标，不仅可以提高PH诊断的准确性，还能有效评估疾病的进展和右心室结构及功能改变。在本研究中，RVEDWT、RVESWT、RVEDD、RVESD、RVWTFT、PAT/PET、PAT具有较好的重测信度和均一性，对PH的诊断具有重要价值。未来，随着多标准化技术和多参数联合评估应用，小动物超声心动图在PH动物模型疾病进展的准确评估及药物筛选研究中将有更广泛的应用前景。
基金
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  • 国家自然科学基金面上项目(82170069)
  • 广东省基础与应用基础研究基金自然科学基金面上项目(2024A1515011208)
  • 广州市科技计划项目2025年度市校（院）企联合资助项目(2025A03J4478)
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2025年第43卷第8期
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doi: 10.3981/j.issn.1000-7857.2024.12.01772
  • 接收时间：2024-12-17
  • 首发时间：2025-06-29
  • 出版时间：2025-04-28
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  • 收稿日期：2024-12-17
  • 修回日期：2025-01-22
  • 录用日期：2025-04-10
基金
国家自然科学基金面上项目(82170069)
广东省基础与应用基础研究基金自然科学基金面上项目(2024A1515011208)
广州市科技计划项目2025年度市校（院）企联合资助项目(2025A03J4478)
作者信息
    呼吸疾病全国重点实验室, 广州呼吸健康研究院, 广州医科大学附属第一医院/国家呼吸医学中心, 广州 510120

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王健（通信作者），教授，研究方向为肺动脉高压发病机制，电子信箱:
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