超声心动图对左室慢性心肌缺血心肌功能及微循环灌注的实验研究
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摘要
背景与目的
缺血性心脏病是常见的心脏疾病,冠状动脉狭窄是其最常见原因(冠心病,coronary artery disease, CAD),临床上慢性心肌缺血比急性缺血更常见。左室收缩功能是判断CAD患者病情的一项重要指标,而左室收缩功能与心肌缺血的程度、范围及有效血流灌注有关。既往研究表明,在发病初期,当局部心肌运动异常时,由于邻近节段心肌代偿,整体功能测值很可能正常,从而误认为心功能正常。因此,准确判断节段心肌的运动功能及血流灌注具有重要作用。
射血分数(ejection fraction, EF)是目前公认的反映左室收缩功能的较好指标。二维超声心动图(two dimensional echocardiography, 2DE)是目前最常用的方法,但当左室形态改变明显时测量误差较大。近年来,实时三维超声心动图(real-time three dimensional echocardiography, RT-3DE)应用新型矩阵型换能器,只需数秒便可形成90°×90°的锥形数据集,实现了真正的实时三维容积数据采集。由于三维探头置于心尖部便可获取全容积数据,不需要移动探头,避免了因探头移动及心动周期偏移导致的测量误差;直接显示左室三维立体形态及进行容积测量,而不需要几何学假设,从根本上克服了2DE的局限,因此测量更准确。RT-3DE能同时分析各节段容积在心动周期中的变化情况,通过分析收缩、舒张末期的节段容积可得到节段EF(segmental EF, SEF)。
心脏有节律地收缩和舒张是维持正常心功能的必要条件。研究已证实,心脏再同步化治疗(cardiac resynchronization therapy,CRT)是改善非同步化患者心功能的有效方法。但是CRT治疗首先需要确定哪些患者会因此获益,即确定非同步化。RT-3DE通过勾划心内膜缘直接显示左室的三维立体形态,准确反映节段容积在心动周期中的变化,在评价左室收缩同步性方面具有潜在的优势。
新近发展起来的超声斑点追踪成像(speckle tracking imaging, STI),通过追踪二维图像上的心肌回声斑点来分析心肌的运动轨迹,可从多个方向评价心肌节段应变,无多普勒应变的角度依赖性。研究表明,STI测量结果与声纳微测仪及心肌加标记磁共振所得结果高度相关,观察者内和观察者间的差异也较小,可重复性好,可靠性较高。左心室室壁运动与其血流灌注情况密切相关,良好的灌注是保证心肌收缩力的必要条件。冠心病患者由于心肌缺血导致心肌代谢异常,从而引起运动异常。近年发展起来的实时心肌声学造影(real-time myocardial contrast echocardiography, RT-MCE),可实时动态显示心肌内微泡从无到有的再充盈过程。经静脉注入造影剂后,因造影剂微泡与红细胞大小相似,可随血流到达心肌组织,分析到达心肌的微泡数量及微泡充盈心肌的速度可反映局部毛细血管床的容量及血流速度,因此,通过探测心肌组织内的微泡显影情况,MCE可从微循环水平定量分析局部心肌的灌注情况。
冠状动脉具有强大的代偿功能,静息状态下,轻度甚至中度狭窄的冠状动脉仍能满足正常供血,因此供血节段可表现为室壁运动正常。通过人为施加负荷,诱发心肌耗氧量增加,狭窄的冠脉供血不能相应增加,相应节段就会出现心肌缺血,此时行超声心动图检查,可发现室壁运动异常,因此有利于发现静息时不能发现的冠心病。小剂量多巴酚丁胺为常用的药物负荷方法,即多巴酚丁胺负荷超声心动图(dobutamine stress echocardiography, DSE)。DSE常与静息状态下的检查进行联合分析,用于评价其静息及负荷状态下的心肌运动及微循环灌注及其储备,可提高诊断的敏感性和准确性。本研究的目的是通过建立冠状动脉左旋支慢性狭窄的动物模型,应用RT-3DE、RT-MCE结合DSE,定量评价缺血后左室节段心肌的收缩、微循环灌注及其储备,并通过STI检查评价缺血后应变和扭转运动的改变。
方法
以10只健康家猪(体重20~26Kg)为研究对象,采用开胸手术在左旋支(Left Circumflex Artery, LCX)近端放置Amerioid缩窄环建立慢性心肌缺血模型。动物麻醉后,取左侧卧位置于检查台上,于模型制作前及术后1～6w每周行RT-3DE、RT-MCE、Vivid 7超声心动图检查。于当日或第二日行选择性冠状动脉造影,冠脉狭窄程度以狭窄血管内径与邻近正常血管内径的百分比表示,并据此将所有动物所有检查进行分组:轻度狭窄组(狭窄<50%),中度狭窄组(狭窄50%～75%),重度狭窄组(狭窄≥75%),建模前正常猪归为对照组。以冠脉狭窄≥90%作为实验终点,以10%氯化钾静注处死动物,取左室行TTC、常规HE、Poley染色及铀-铅双染色电镜检查,观察其病理变化。
1.模型建立简要步骤
氯胺酮300mg(约15mg//Kg)、速眠新20mg和阿托品1mg肌肉注射诱导麻醉,气管插管,接呼吸机及心电监护仪,静脉与吸入复合麻醉维持,左胸第4肋间切开10厘米进胸。于LCX起始部置入内径2.25mm的Ameroid缩窄环,以无菌塑料束带环绕Ameroid缩窄环。缝合心包,逐层关胸。
2.实时三维及心肌声学造影图像采集及分析
动物取左侧卧位,连接肢体导联心电图。RT-3DE检查使用Philips iE33彩色超声诊断仪,X3-1探头,于心尖区获取全容积三维数据图像,对图像质量欠佳者,于注射造影剂后再采集图像。RT-MCE采用iE33 S5-1探头,采集胸骨旁左室中部层面短轴观图像,造影剂为本实验室自制“脂氟显”,剂量0.02ml/kg。选心肌造影模式,机械指数(MI) 0.1,Beats 20。图像采集完成后,以微量输液泵经静脉持续注入小剂量多巴酚丁胺,逐渐增加剂量直至靶心率较负荷前增加20bpm左右,重复上述RT-3DE及RT-MCE采图。
图像拷贝至QLAB 5.2工作站进行脱机分析。以3DQ及3DQA软件分析实时三维图像,软件自动得出左室整体EF及各节段EDV、ESV等参数,计算节段EF (SEF)。软件并分析左室节段间达最小容积时间(Time to minimal segmental volume, Tmsv),得到左室多节段间Tmsv的最大差值Tmsv-dif、标准差Tmsv-SD及其标化值(以占心动周期的百分比表示,便于不同心率受检者之间比较),以判断左室内收缩同步性。造影图像采用ROI进行定量分析,评价节段微循环灌注,参数包括A值、β值、A×β值,分别反映局部心肌血容量、心肌内血流速度及局部心肌血流量。将上述各参数负荷后与负荷前的比值定义为储备值,用于评价收缩及灌注储备功能。
3.二维应变图像采集及分析
使用GE Vivid 7彩色超声诊断仪,M3S探头,谐波频率,帧频≥50帧/s。采集胸骨旁左室系列短轴(二尖瓣环、乳头肌、心尖平面)连续三个心动周期图像,分别代表左室基底部、中部和心尖部,各平面依次分为前间隔、前壁、侧壁、后壁、下壁和后间隔6个节段。以Echo PAC软件进行分析,自动得出各节段心肌径向应变峰值(peak radial strain, RS)、环向(或圆周)应变峰值(peak circumferencial strain, CS)、及收缩期旋转角度峰值(peak systolic rotation angle, Rot),以心尖与二尖瓣平面峰值旋转角度之差值反映左室扭转运动角度(Tor)。探讨心肌节段二维应变及各节段旋转运动及左室扭转角度的改变。
4.99mTc-MIBI门控心肌灌注显像及图像分析
于超声心动图检查后1～3天行核素检查。使用GE Infinia Hawkeye SPECT仪,低能高分辨准直器,采用Two Day法行静息及负荷门控心肌灌注断层显像。首日经猪耳静脉注射15mCi 99mTc-MIBI后约1.5小时后行静息扫描,次日行负荷扫描。实验过程中方法和参数设置不变。
应用Emory Cardiac Toolbox for cardiac (ECTb)进行定量分析。软件自动得出EDV、ESV、SV、EF等心功能参数及左室肌块质量(LV Mass)。与超声图像相对应,将左室短轴图像以右心室为标志,顺时针方向依次分为6个节段,测量并记录各节段感兴趣区放射性计数,评价心肌灌注。
5.统计学分析
使用SPSS 13.0统计软件包进行分析。参数用均数±标准差(x±S)表示,负荷前后比较采用配对T检验,多组间比较采用单因方差分析(ONE-WAY ANOVA),用LSD法进行均数间多重比较。以p<0.05为差异有统计学意义,以p<0.01为差异有显著统计学意义。
结果
1.模型建立及分组
10只猪中有8只成功建立模型。所有动物于第6周末以前结束检查,8只猪于建模后1～6周共行超声心动图检查38例次。图像质量欠佳不能用于分析者予以排除, 35例次纳入统计分析。所有检查依照LCX狭窄程度进行分组,轻、中、重度狭窄组分别为12例次、12例次、11例次。术前10例为对照组。
2.RT-3DE定量节段分析
(1)负荷前后比较,重度狭窄组负荷后左心室整体射血分数(EF)及多数节段射血分数(SEF)较静息时降低,其余三组升高,差异有统计学意义(p<0.05,0.01)。
(2)静息及负荷状态下,左室SEF随狭窄程度增加呈降低趋势。缺血节段:静息及负荷状态下,中、重度狭窄组二尖瓣及乳头肌平面左旋支供血的侧壁和后壁SEF较对照组及轻度狭窄组降低;负荷状态下,轻度狭窄组二尖瓣平面侧壁和后壁、重度狭窄组心尖平面侧壁和下壁SEF也较对照组降低,差异有统计学意义(p<0.05,0.01)。
非缺血节段比较:负荷后重度狭窄组二尖瓣及乳头肌平面前壁和下壁SEF较对照组降低,差异有统计学意义(p<0.05)。
(3)SEF储备值比较:缺血节段SEF储备值随狭窄程度增加呈降低趋势。中、重度狭窄组各平面侧壁、后壁SEF储备值与对照组比较,差异有统计学意义(p<0.05,0.01)。重度狭窄组二尖瓣及乳头肌平面非缺血节段中前壁、下壁、心尖平面下壁SEF储备值较对照组降低,差异有统计学意义(p<0.05,0.01)。
(4)同步化评价:RT-3DE定量分析左室多个节段间达最小容积时间之最大差值、标准差及其标化值,结果表明,中、重度狭窄组较普遍存在左室收缩不同步,轻度狭窄组收缩不同步表现在左室基底部。
3.定量MCE分析
(1)负荷前后比较:重度狭窄组负荷后缺血节段(侧壁和后壁)A值、A×β值较负荷前降低,其余节段β值、A×β值增高,差异有统计学意义(p<0.05,0.01)。而对照组、轻、中度狭窄组负荷后各节段各灌注参数(心肌血容量A值、速度β值、心肌血流量A×β值)高于静息状态。
(2)静息时中度和重度狭窄组缺血节段各灌注参数较对照组降低,负荷后各狭窄组均较对照组降低,差异有统计学意义(p<0.05,0.01)。静息时重度狭窄组非缺血节段之前壁和下壁A×β值较其余三组升高,差异有统计学意义(p<0.05);负荷后重度狭窄组前壁A×β值、中度狭窄组前壁和下壁A×β值较对照组降低,差异有统计学意义(P<0.05,0.01)。
(3)灌注储备值比较:轻度狭窄组缺血节段A×β储备值、中度狭窄组β储备值及A×β储备值、重度狭窄组各储备值较对照组降低,差异有统计学意义(p<0.01)。重度狭窄组前壁β储备值和A×β储备值、下壁A×β储备值较对照组降低,差异有统计学意义(P<0.05)。
(4)静息及负荷状态下RT-MCE所测各组各节段血流量(A×β)与SPECT所测放射性计数相关性好(P<0.05,0.01)。
4.二维应变与扭转运动分析
(1)径向应变为正向波形,环向应变为负向波形,随狭窄程度增加径向应变峰值(RS)、环向应变峰值(CS)呈逐渐降低趋势。
缺血节段比较:重度狭窄组各平面侧壁和后壁RS和CS较对照组和轻度狭窄组降低,中度狭窄组各平面侧壁和后壁RS和CS较对照组降低,差异有统计学意义(p<0.05,0.01)。
非缺血节段比较:重度狭窄组各平面前壁RS和CS、二尖瓣及乳头肌平面下壁RS较对照组降低,中度狭窄组乳头肌平面前壁和下壁RS较对照组降低,差异有统计学意义(p<0.05,0.01)。
(2)对照组心尖及二尖瓣平面各节段旋转曲线形态较为一致,即心尖平面呈逆时针方向旋转,旋转角度(Rot)为正值;二尖瓣平面为顺时针方向旋转,Rot为负值。各狭窄组心尖及二尖瓣平面旋转方向与对照组基本一致。
缺血节段比较:与对照组比较,重度狭窄组各平面、中度狭窄组二尖瓣和乳头肌平面、轻度狭窄组二尖瓣平面侧壁和后壁Rot降低,差异有统计学意义(p<0.05,0.01)。中度和重度狭窄组各平面侧壁和后壁Rot较轻度狭窄组降低,差异有统计学意义(p<0.05,0.01)。
非缺血节段:中度和重度狭窄组二尖瓣平面前壁、重度狭窄组乳头肌平面前壁Rot较对照组降低,差异有统计学意义(p<0.05)。
(3)左室扭转角度(心尖与二尖瓣平面收缩期峰值旋转角度之差值)比较:中度和重度狭窄组侧壁和后壁之扭转角度较对照组和轻度狭窄组降低,差异有统计学意义(p<0.05)。重度狭窄组前壁扭转角度较对照组降低,差异有统计学意义(p<0.05)。
结论
1.开胸法于家猪冠状动脉左旋支近端置入Ameroid缩窄环,经冠状动脉造影证实可成功制备慢性心肌缺血模型,方法可靠。
2.定量分析表明,随狭窄程度逐渐增加,缺血节段射血分数和定量灌注参数呈逐渐降低趋势。中度和重度狭窄组与对照组比较,差异有统计学意义。
3.RT-MCE所测血流量与SPECT所测放射性计数相关性好。冠状动脉在正常状态下具有良好的储备能力。轻、中度狭窄组缺血节段心肌仍存在储备能力,但储备值分析发现,其储备能力较正常组降低。重度狭窄组缺血节段收缩功能及灌注指标降低、储备能力丧失,非缺血节段储备值也降低。
4.实时三维超声心动图通过定量分析左室多个节段间达最小容积时间之最大差值、标准差及其标化值,可评价左室内机械不同步性,标化值较绝对值能更敏感地发现收缩不同步。
5.随狭窄程度进行性增加,缺血节段径向及环向应变、旋转角度均呈逐渐降低趋势,中、重度狭窄组缺血区多数节段应变及旋转角度较对照组降低。
6.超声斑点追踪成像、实时三维超声心动图、实时心肌声学造影从不同方面反映心肌缺血后左室各节段心肌的运动及微循环灌注的变化,联合应用负荷试验可评价静息及负荷状态下的运动及微循环灌注改变及其储备,显示静息状态未显示的一些异常,提高诊断敏感性。
Backgrounds and Objectives
Ischemic heart disease is one kind of the most common heart diseases and coronary artery stenosis is the most common cause, which is called coronary artery disease (CAD). Chronic ischemia is more often occurred than the acute in clinical. Left ventricular (LV) systolic function is important in the diagnosis of CAD, and is related to the severity and range of myocardial ischemia and to effective blood perfusion. However, in the early phase of myocardial ischemia, when the regional wall motion has been changed, the global function may be still in the normal range owing to the compensation of the segment near to the ischemic territory and would be mistaken to normal. So the quantitative assessment of regional myocardial wall motion and blood perfusion plays important role in the diagnosis of CAD. Recent updates in the field of echocardiography have resulted in improvements in both image quality and techniques permitting simultaneous assessment of global and regional myocardial structure, function, and perfusion, enabling non-invasive assessment of coronary artery disease.
When echocardiography quantifying LV systolic function, LV ejection fraction (EF) is the most commonly used index. Two-dimensional echocardiography (2DE) is the most common technique, but it has pitfalls when LV morphology changed obviously. Recently, real-time three-dimensional echocardiography (RT-3DE) could acquire full volume data within only several seconds, enabling truly real time three dimensional data acquisition. And full volume data could be obtained with probe located at apical region, avoiding measurement error coming from the change of probe location and the different cardiac cycle. Further more, RT-3DE displays directly LV three dimensional morphology and then calculate LV volume directly, need no geometry hypothesis, as is in the 2-DE, so it conquer the limitation of 2-DE. RT-3DE analyzes all segmental volumes during the same cardiac cycle, and calculates segmental EF (SEF) from segmental volume of end diastole and end systole.
Rhythmic LV contraction and relaxation is necessary to maintain normal cardiac function. Cardiac resynchronization therapy has been proved effective in improving cardiac function of the patients of LV contractile dyssynchrony. But the problem is how to determine LV contractile dyssynchrony. RT-3DE outline LV endocardium and display directly the 3-dimensional morphology, reflect accurate LV volume change during cardiac cycle, so has potential superiority in evaluating LV synchronization.
More recently, speckle tracking echocardiography, a new echocardiographic 2-dimensional (2D) strain technique based on automatic tracking the two-dimensional motion of characteristic speckle patterns in B-mode images, enables simultaneous valuation of regional myocardial strain in both the radial and circumferential directions (i.e., circumferential strain (CS), and radial strain (RS) ) from parasternal short-axis view. Two-dimensional strain is in principle angle independent, and has been shown to be repeatable and reproducible, and accurate and correlate well with sonomicrometry and magnetic resonance imaging tagging during ischemia.
Normal LV myocardial contractility depends on sufficient blood perfusion. Ischemia leads to abnormal myocardial metabolism and then to abnormal myocardial contractility in CAD. Real-time myocardial contrast echocardiography (RT-MCE) is a newly developed technique to quantify myocardial blood perfusion, displaying the replenishment process of microbubbles into myocardium after microbubbles being destroyed by a high energy pulse. The replenishment of contrast can be characterized by a time-intensity curve (i.e. destruction–refilling curve), which can be fitted to a monoexponential function: y=A×(1-eβt)+C. The plateau value (A) of the replenishment curve reflects the myocardial blood volume, and the slope (β) reflects the reappearance rate of microbubbles (i.e. myocardial microbubble velocity). The product of A×βtherefore represents myocardial blood flow. Thus RT-MCE could analyze quantitively the microvascular blood perfusion in regions of interest in myocardium with specialist software.
Conronary artery has powerful compensation capacity, so mild to moderate stenosed coronary vessel will supply adequate blood to maintain normal function at rest, so echocardigraphy may display no abnormality in LV wall motion and perfusion. Stress will induce an increase of myocardial consumption of oxygen, but in stenosed artery the blood supply could not increase accordingly, leading to ischemia in the victim territory, therefore abnormal wall motion and perfuison will be found in echocardiography. Dobutaming stress echocardiography (DSE) is one of the favorite stress methods, and is often applied to 2DE, RT-3DE or RT-MCE and combined with baseline, to evaluate the myocardial motion or blood perfusion in both stress and rest condition and further to evaluate the reserves, thus increases the technique's sensitivity and accuracy, and has potential to anticipate prognosis.
In the present study, chronic myocardial ischemia was induced by placing an Ameroid constrictor in the left circumflex in swines, then RT-3DE and RT-MCE examination combining rest and DSE was performed to ascertain chronic ischaemic LV dysfunction and myocardial perfusion and reserves, and Vivid 7 was used to assess 2 dimensional strain and torsional anomalies, so as to validate the role of Echocardiography to recognize regional contractile variations and perfusional anomalies for the detection of ischemia.
Methods
A chronic ischemic model was induced and echocardiography and coronary angiography was performed as described below before LCX constriction, every week after LCX constriction, until the LCX stenosis was of≥90% validated coronary angiographically. Then animals were killed, hearts were harvested and processed for hematoxylin and eosin (HE) stain, Poley stain and scanning electron microscopy.
Chronic ischemic model and Animal preparation
Ten normal juvenile domestic swines in either gender, body weight 20 to 26Kg, were subjected to induce chronic ischemia by constricting the left circumflex artery (LCX) with Ameroid constrictor. Pigs were sedated with an intramuscular injection of 300mg ketamine (about 15mg/Kg) with 5mg midazolam and 1mg atropine, intubated, and maintained with combined anesthesia with inhalant enflurane and intravenous vecuronium bromide. A thoracotomy was performed through the fourth left intercostal space. The pericardium was opened and an Ameroid constrictor was placed around the proximal LCX just distal to the main stem of the left coronary artery. The chest was then closed, and the animals were allowed to recover and returned to their cages. This animal experiment was approved by the Animal Care Committee of Third Military Medical University.
RT-3DE and RT-MCE Echocardiographic data acquisition
General anesthesia was initiated with ketamine (15mg/Kg) with 1mg atropine intramuscular, and maintained with intravenous ketamine or intraperitoneal pentobarbital. Animals were investigated in the closed-chest state in the left lateral decubitus position. All RT-3DE Full Volume echocardiograms were obtained with iE33 ultrasound machine (Philips Medical Systems) with Probe X3-1, with Probe located at apical area. If the border was unclear, ZhiFuXian—a homemade contrast agent in our laboratory was infused to enhance the resolution. RT-MCE contrast images of parasternal short axis at PM level were acquired with iE33 machine, S5 probe. The LVO pattern was select and set as second harmonic (transmit/receive: 1.7/3.4 MHz), mechanic index 0.1, beats 20.
Images were copied to QLAB 5.2 postprocess workstation, and 3DQ and 3DQA software was used to analyze Full Volume data sets, and LV global ejection fraction (EF) and EDV and ESV of 16 segments except for apex were yielded, and then segmental EF (SEF) were calculated with EXCEL. Software 3DQA provided the maxium difference of Tmsv (Tmsv-dif) and standard deviation (Tmsv-SD) among various segments and standard index (Tmsv-dif% and Tmsv-SD%), to evaluate LV dyssynchrony. ROI software were used to analyze contrast images, and yielded the plateau value A of the replenishment curve (A reflects the myocardial blood volume), the slopeβ(βreflects the myocardial velocity). Calculate the product of A×β( A×βrepresents myocardial blood flow).
DSE images acquisition and data analysis
After the RT-3DE and RT-MCE images were acquired, dobutamine was administered intravenous by micro-infusion pump according to the low-dose protocol (5μg/kg/min followed by 10μg/kg/min, each step lasting 5 min). When target heart rate increased to 20bpm higher than that of baseline, repeated the baseline image acquisition. The reserve was determined as the ratio of the data of stress to that of the baseline, including SEF reserve, A reserve,βreserve, and A×βreserve, reflecting the contractile and perfusion reserve function. Each data was an average of two measurements.
Two-dimensional Strain imaging and data analysis
Animals anesthesia and prepare as before. A Vivid 7 (GE Medical Systems) was used to acquire 2D strain images data with a M3S Probe. B-mode second harmonic images (frame rate≥50 frames/s) were recorded in parasternal apical, middle and basal short axis views of three consecutive cardiac cycles. The digital data were stored and transferred to a computer for subsequent offline analyses.
Digital data were transferred to a dedicated software EchoPac (GE Medical Systems) for subsequent offline analysis. Each level of LV was divided into six segments, and each segment was individually analyzed. Two-dimensional peak radial and circumferential strains during systole were measured. By tracing the endocardial contour on an end-diastolic frame, the software will automatically track the contour on subsequent frames. Adequate tracking can be verified in real-time and corrected by adjusting the region of interest semi-manually to ensure optimal tracking. Circumferential strain (CS) and radial strain (RS) were recorded. At the same time, left ventricular rotation at apical and basal level of each wall and LV torsion were analyzed. The rotation difference between apical level and mitral level reflected the LV torsional angle (Tor).
Selective coronary angiography
Selective coronary angiography was performed the same day as or the day after the echocardiography to confirm the stenosis degree of LCX. Quantitative coronary angiography was performed through cine review by two blinded experienced angiographers. The stenosis at site of Ameroid placement was calculated by the following equation: (1 ? lumen diameter stenotic site/lumen diameter reference)×100. The severity of LCX stenosis were grouped into mild stenosis (stenosis <50%), moderate stenosis (stenosis 50~75%) and severe stenosis (stenosis≥75%).
Gated SPECT myocardium perfusion imaging and data analysis
99mTc-MIBI Gated SPECT myocardium perfusion imaging was performed with Infinia Hawkeye SPECT instrument (GE Medical Systems) 1 to 3 day after Echocardiogram. Two day method was used to perform rest/stress scan, with scanning at rest performed 90 min after intravenous infusion 15mCi 99mTc-MIBI on first day, then scanning the same way at stress on the second day.
Emory Cardiac Toolbox for cardiac was used to analyze the Dicom data. LV functional parameters and LV mass was yielded. Region of interest was set at the center of 6 segments at LV short axis corresponding to echogram, radioactive counting was then measured. Statistical analysis
Data were expressed as mean±SD. Statistical analysis was performed with SPSS 13.0 software. Measurements values were grouped by the severity of LCX stenosis verified by selective coronary angiography and their means were compared. Measurements of at rest and stress were compared by a paired Student t test. Multiple comparisons between different groups were performed using ONE-WAY ANOVA analysis followed by post-hoc least-significant difference test. A p<0.05 was considered statistically significant for all analysis.
Results
Animal models and animal group
Of the 10 subjects, 8 were induced chronic ischemia successfully and each was showed severe stenosis of LCX 4 to 6 weeks after placement of an Ameroid constrictor verified by quantitative coronary angiography analysis. Total times of echocardiography examination of all the 8 pigs from 1 to 6 weeks post operation were 38, of which 3 were excluded owing to unclear images, and 35 times were included in analysis, of which mild, moderate and severe stenosis were 12, 12 and 11 times respectively, according to the coronary angiography. Ten normal pigs before operation served as controls.
RT-3DE variables
Compared with baseline, the global ejection fraction (EF) and segmental ejection fraction (SEF) of most segments in severe stenosis decreased in stress condition, while that in control, mild and moderate stenosis increased (p<0.05, 0.01).
LV SEF showed a tendency of gradually decrease according to the progressive LCX stenosis under both baseline and stress condition.
SEF of LCX territory region compare among groups: under both baseline and stress condition, SEF of lateral and posterior wall at mitral and papillary muscle (PM) level decreased significantly in moderate and severe stenosis, compared with control and mild stenosis. At stress, SEF of lateral and inferior wall at apical level in severe stenosis and SEF of lateral and posterior wall at mitral level in mild stenosis decreased, compared with control. (p<0.05, 0.01).
SEF of LAD and RCA territory region compare among groups: SEF of anterior and inferior wall at mitral and PM level decreased significantly in severe stenosis at stress, compared with control. (p<0.05).
SEF reserve compare among groups: SEF reserve had a tendency of gradually decrease along with the progress of LCX stenosis. SEF reserve of lateral and posterior wall at all levels decreased significantly in moderate and severe stenosis, compared with control. Among the LAD and RCA segments, anterior and inferior wall at mitral and PM level and inferior wall at apical level showed marked decrease of SEF reserve in severe stenosis, compared with control (p<0.05, 0.01).
Synchrony evaluation: RT-3DE analyzed quantitively the maximum difference and standard deviation of time to minimal segmental volume (Tmsv) among segments. The results indicated that RT-3DE in healthy controls showed highly synchronous contraction in contrast to widespread dyssynchrony found in subjects of moderate and severe stenosis, and dyssynchrony found only in basal segments in mild stenosis.
RT-MCE variables
Compared with baseline, A and A×βof lateral wall and posterior wall decreased obviously, andβand A×βof other segments increased under stress in severe stenosis (p<0.05,0.01). By contrast, all perfusion variables (A,βand A×β) of all segments in other groups increased (p<0.05, 0.01).
Perfusion parameters of LCX territory region compared among groups: all perfusion variables of lateral and posterior wall decreased significantly in moderate and severe stenosis at rest, compared with control. By contrast, those variables decreased in all stenosis groups at stress, and statistical difference was found among all stenosis groups. (p<0.05, 0.01).
Perfusion parameters of other segments compare among groups: at rest A×βof anterior and inferior wall in severe stenosis increased significantly, compared with other groups (p<0.05, 0.01). At stress A×βof anterior wall in severe stenosis and A×βof anterior and inferior wall in moderate stenosis decreased significantly, compared with control (p<0.05).
Perfusion reserve variables compare: A×βreserve of lateral and posterior wall in mild stenosis,βand A×βreserve in moderate stenosis and reserves of A,β, and A×βin severe stenosis decreased significantly, compared with control (p<0.05, 0.01). Of nonischemic segments, anterior wall demonstrated decreasedβand A×βreserve and inferior wall decreased A×βreserve in severe stenosis, compared with control (p<0.05).
Under both rest and stress condition, myocardial blood flow of all segments in each group measured by RT-MCE correlated well with radioactive counting by SPECT (all p<0.05, 0.01).
Two-dimensional Strain and torsion variables
1. The circumferential strain curve was positive wave form, and radial strain curve was negative. The peak value of the circumferential strain curve (CS) and radial strain curve (RS) had a tendency of gradually decrease according to the progressive stenosis. LCX segments compare among groups: RS and CS of lateral and posterior wall decreased significantly at all levels in severe stenosis, compared with control and mild stenosis; and decreased significantly at all levels in moderate stenosis, and at mitral level in mild stenosis, compared with control (p<0.05, 0.01).
LAD and RCA segments compare among groups: compared with control, RS and CS of anterior wall at all levels and RS of inferior wall at mitral and PM levels in severe stenosis decreased significantly, while RS of anterior and inferior wall at PM level in moderate stenosis decreased significantly (p<0.05, 0.01).
2. At apical and mitral level, rotation curve of each segment of LV had homogeneous wave form, i.e., LV rotated counterclockwise at apical level (positive angle) and rotated clockwise at mitral level (negative angle). LCX stenosis groups had almost the same rotation direction at both apical and mitral level like that of control.
LCX segments compare among groups: Rotation angle of lateral and posterior wall at all levels in severe stenosis, at mitral and PM level in moderate stenosis, and at mitral level in mild stenosis decreased significantly, compared with control (p<0.05, 0.01). Rotation angle of lateral and posterior wall at all levels in moderate and severe stenosis also decreased significantly, compared with mild stenosis (p<0.05,0.01).
Nonischemic segments compare among groups: Rotation angle of anterior wall at mitral level in moderate and severe stenosis and of anterior wall at PM level in severe stenosis decreased significantly, compared with control (p<0.05).
3. Torsional angle (Tor) compare: Torsional angle of lateral and posterior wall in moderate and severe stenosis decreased significantly, compared with control and mild stenosis (p<0.05). Compared with control, Tor of anterior wall in severe stenosis decreased significantly (p<0.05).
Conclusions
1. Chronic ischemia model induced by placing an Ameroid constrictor at the left circumflex artery (LCX) is angiographically documented.
2. Quantitative analysis indicates that along with progressive stenosis, segmental ejection fraction and perfusion parameters of ischemic segments decrease gradually. There is statistical difference of those parameters in moderate and severe stenosis compared with control.
3. A linear relationship exists between myocardial blood flow measured by RT-MCE and radioactive counting by SPECT. Normal coronary artery has sufficient reserve capacity. Although territories supplied by mild and moderate stenotic LCX still have some reserve ability, they are impaired according to reserve analysis. Segments supplied by severe stenotic LCX demonstrate decreased myocardial contractility and perfusion and exhausted reserve capacity, company by impaired reserve capacity of nonischemic regions.
4. RT-3DE could evaluate LV dyssynchrony by analyzing the maximum difference and standard deviation and standard variables of time to minimal segmental volume, and standard variable is found more sensitive than the absolute time value.
5. Along with progressive stenosis, circumferential strain, radial strain and rotation angle show progressive decrease tendency. Most segments of the victim regions in moderate and severe stenosis decrease markedly than that of control.
6. Real-time three-dimensional echocardiography, real-time myocardial contrast echocardiography and speckle tracking echocardiography reflect various aspects of LV segmental wall motion and microvascular perfusion. Combining assessment parameters at baseline and dobutaming stress, they could evaluate the myocardial motion or blood perfusion during both rest and stress condition and further to evaluate the reserves, finding indications concealed at sole rest, thus increases the techniques' diagnostic sensitivity.
缺血性心脏病是常见的心脏疾病,冠状动脉狭窄是其最常见原因(冠心病,coronary artery disease, CAD),临床上慢性心肌缺血比急性缺血更常见。左室收缩功能是判断CAD患者病情的一项重要指标,而左室收缩功能与心肌缺血的程度、范围及有效血流灌注有关。既往研究表明,在发病初期,当局部心肌运动异常时,由于邻近节段心肌代偿,整体功能测值很可能正常,从而误认为心功能正常。因此,准确判断节段心肌的运动功能及血流灌注具有重要作用。
射血分数(ejection fraction, EF)是目前公认的反映左室收缩功能的较好指标。二维超声心动图(two dimensional echocardiography, 2DE)是目前最常用的方法,但当左室形态改变明显时测量误差较大。近年来,实时三维超声心动图(real-time three dimensional echocardiography, RT-3DE)应用新型矩阵型换能器,只需数秒便可形成90°×90°的锥形数据集,实现了真正的实时三维容积数据采集。由于三维探头置于心尖部便可获取全容积数据,不需要移动探头,避免了因探头移动及心动周期偏移导致的测量误差;直接显示左室三维立体形态及进行容积测量,而不需要几何学假设,从根本上克服了2DE的局限,因此测量更准确。RT-3DE能同时分析各节段容积在心动周期中的变化情况,通过分析收缩、舒张末期的节段容积可得到节段EF(segmental EF, SEF)。
心脏有节律地收缩和舒张是维持正常心功能的必要条件。研究已证实,心脏再同步化治疗(cardiac resynchronization therapy,CRT)是改善非同步化患者心功能的有效方法。但是CRT治疗首先需要确定哪些患者会因此获益,即确定非同步化。RT-3DE通过勾划心内膜缘直接显示左室的三维立体形态,准确反映节段容积在心动周期中的变化,在评价左室收缩同步性方面具有潜在的优势。
新近发展起来的超声斑点追踪成像(speckle tracking imaging, STI),通过追踪二维图像上的心肌回声斑点来分析心肌的运动轨迹,可从多个方向评价心肌节段应变,无多普勒应变的角度依赖性。研究表明,STI测量结果与声纳微测仪及心肌加标记磁共振所得结果高度相关,观察者内和观察者间的差异也较小,可重复性好,可靠性较高。左心室室壁运动与其血流灌注情况密切相关,良好的灌注是保证心肌收缩力的必要条件。冠心病患者由于心肌缺血导致心肌代谢异常,从而引起运动异常。近年发展起来的实时心肌声学造影(real-time myocardial contrast echocardiography, RT-MCE),可实时动态显示心肌内微泡从无到有的再充盈过程。经静脉注入造影剂后,因造影剂微泡与红细胞大小相似,可随血流到达心肌组织,分析到达心肌的微泡数量及微泡充盈心肌的速度可反映局部毛细血管床的容量及血流速度,因此,通过探测心肌组织内的微泡显影情况,MCE可从微循环水平定量分析局部心肌的灌注情况。
冠状动脉具有强大的代偿功能,静息状态下,轻度甚至中度狭窄的冠状动脉仍能满足正常供血,因此供血节段可表现为室壁运动正常。通过人为施加负荷,诱发心肌耗氧量增加,狭窄的冠脉供血不能相应增加,相应节段就会出现心肌缺血,此时行超声心动图检查,可发现室壁运动异常,因此有利于发现静息时不能发现的冠心病。小剂量多巴酚丁胺为常用的药物负荷方法,即多巴酚丁胺负荷超声心动图(dobutamine stress echocardiography, DSE)。DSE常与静息状态下的检查进行联合分析,用于评价其静息及负荷状态下的心肌运动及微循环灌注及其储备,可提高诊断的敏感性和准确性。本研究的目的是通过建立冠状动脉左旋支慢性狭窄的动物模型,应用RT-3DE、RT-MCE结合DSE,定量评价缺血后左室节段心肌的收缩、微循环灌注及其储备,并通过STI检查评价缺血后应变和扭转运动的改变。
方法
以10只健康家猪(体重20~26Kg)为研究对象,采用开胸手术在左旋支(Left Circumflex Artery, LCX)近端放置Amerioid缩窄环建立慢性心肌缺血模型。动物麻醉后,取左侧卧位置于检查台上,于模型制作前及术后1～6w每周行RT-3DE、RT-MCE、Vivid 7超声心动图检查。于当日或第二日行选择性冠状动脉造影,冠脉狭窄程度以狭窄血管内径与邻近正常血管内径的百分比表示,并据此将所有动物所有检查进行分组:轻度狭窄组(狭窄<50%),中度狭窄组(狭窄50%～75%),重度狭窄组(狭窄≥75%),建模前正常猪归为对照组。以冠脉狭窄≥90%作为实验终点,以10%氯化钾静注处死动物,取左室行TTC、常规HE、Poley染色及铀-铅双染色电镜检查,观察其病理变化。
1.模型建立简要步骤
氯胺酮300mg(约15mg//Kg)、速眠新20mg和阿托品1mg肌肉注射诱导麻醉,气管插管,接呼吸机及心电监护仪,静脉与吸入复合麻醉维持,左胸第4肋间切开10厘米进胸。于LCX起始部置入内径2.25mm的Ameroid缩窄环,以无菌塑料束带环绕Ameroid缩窄环。缝合心包,逐层关胸。
2.实时三维及心肌声学造影图像采集及分析
动物取左侧卧位,连接肢体导联心电图。RT-3DE检查使用Philips iE33彩色超声诊断仪,X3-1探头,于心尖区获取全容积三维数据图像,对图像质量欠佳者,于注射造影剂后再采集图像。RT-MCE采用iE33 S5-1探头,采集胸骨旁左室中部层面短轴观图像,造影剂为本实验室自制“脂氟显”,剂量0.02ml/kg。选心肌造影模式,机械指数(MI) 0.1,Beats 20。图像采集完成后,以微量输液泵经静脉持续注入小剂量多巴酚丁胺,逐渐增加剂量直至靶心率较负荷前增加20bpm左右,重复上述RT-3DE及RT-MCE采图。
图像拷贝至QLAB 5.2工作站进行脱机分析。以3DQ及3DQA软件分析实时三维图像,软件自动得出左室整体EF及各节段EDV、ESV等参数,计算节段EF (SEF)。软件并分析左室节段间达最小容积时间(Time to minimal segmental volume, Tmsv),得到左室多节段间Tmsv的最大差值Tmsv-dif、标准差Tmsv-SD及其标化值(以占心动周期的百分比表示,便于不同心率受检者之间比较),以判断左室内收缩同步性。造影图像采用ROI进行定量分析,评价节段微循环灌注,参数包括A值、β值、A×β值,分别反映局部心肌血容量、心肌内血流速度及局部心肌血流量。将上述各参数负荷后与负荷前的比值定义为储备值,用于评价收缩及灌注储备功能。
3.二维应变图像采集及分析
使用GE Vivid 7彩色超声诊断仪,M3S探头,谐波频率,帧频≥50帧/s。采集胸骨旁左室系列短轴(二尖瓣环、乳头肌、心尖平面)连续三个心动周期图像,分别代表左室基底部、中部和心尖部,各平面依次分为前间隔、前壁、侧壁、后壁、下壁和后间隔6个节段。以Echo PAC软件进行分析,自动得出各节段心肌径向应变峰值(peak radial strain, RS)、环向(或圆周)应变峰值(peak circumferencial strain, CS)、及收缩期旋转角度峰值(peak systolic rotation angle, Rot),以心尖与二尖瓣平面峰值旋转角度之差值反映左室扭转运动角度(Tor)。探讨心肌节段二维应变及各节段旋转运动及左室扭转角度的改变。
4.99mTc-MIBI门控心肌灌注显像及图像分析
于超声心动图检查后1～3天行核素检查。使用GE Infinia Hawkeye SPECT仪,低能高分辨准直器,采用Two Day法行静息及负荷门控心肌灌注断层显像。首日经猪耳静脉注射15mCi 99mTc-MIBI后约1.5小时后行静息扫描,次日行负荷扫描。实验过程中方法和参数设置不变。
应用Emory Cardiac Toolbox for cardiac (ECTb)进行定量分析。软件自动得出EDV、ESV、SV、EF等心功能参数及左室肌块质量(LV Mass)。与超声图像相对应,将左室短轴图像以右心室为标志,顺时针方向依次分为6个节段,测量并记录各节段感兴趣区放射性计数,评价心肌灌注。
5.统计学分析
使用SPSS 13.0统计软件包进行分析。参数用均数±标准差(x±S)表示,负荷前后比较采用配对T检验,多组间比较采用单因方差分析(ONE-WAY ANOVA),用LSD法进行均数间多重比较。以p<0.05为差异有统计学意义,以p<0.01为差异有显著统计学意义。
结果
1.模型建立及分组
10只猪中有8只成功建立模型。所有动物于第6周末以前结束检查,8只猪于建模后1～6周共行超声心动图检查38例次。图像质量欠佳不能用于分析者予以排除, 35例次纳入统计分析。所有检查依照LCX狭窄程度进行分组,轻、中、重度狭窄组分别为12例次、12例次、11例次。术前10例为对照组。
2.RT-3DE定量节段分析
(1)负荷前后比较,重度狭窄组负荷后左心室整体射血分数(EF)及多数节段射血分数(SEF)较静息时降低,其余三组升高,差异有统计学意义(p<0.05,0.01)。
(2)静息及负荷状态下,左室SEF随狭窄程度增加呈降低趋势。缺血节段:静息及负荷状态下,中、重度狭窄组二尖瓣及乳头肌平面左旋支供血的侧壁和后壁SEF较对照组及轻度狭窄组降低;负荷状态下,轻度狭窄组二尖瓣平面侧壁和后壁、重度狭窄组心尖平面侧壁和下壁SEF也较对照组降低,差异有统计学意义(p<0.05,0.01)。
非缺血节段比较:负荷后重度狭窄组二尖瓣及乳头肌平面前壁和下壁SEF较对照组降低,差异有统计学意义(p<0.05)。
(3)SEF储备值比较:缺血节段SEF储备值随狭窄程度增加呈降低趋势。中、重度狭窄组各平面侧壁、后壁SEF储备值与对照组比较,差异有统计学意义(p<0.05,0.01)。重度狭窄组二尖瓣及乳头肌平面非缺血节段中前壁、下壁、心尖平面下壁SEF储备值较对照组降低,差异有统计学意义(p<0.05,0.01)。
(4)同步化评价:RT-3DE定量分析左室多个节段间达最小容积时间之最大差值、标准差及其标化值,结果表明,中、重度狭窄组较普遍存在左室收缩不同步,轻度狭窄组收缩不同步表现在左室基底部。
3.定量MCE分析
(1)负荷前后比较:重度狭窄组负荷后缺血节段(侧壁和后壁)A值、A×β值较负荷前降低,其余节段β值、A×β值增高,差异有统计学意义(p<0.05,0.01)。而对照组、轻、中度狭窄组负荷后各节段各灌注参数(心肌血容量A值、速度β值、心肌血流量A×β值)高于静息状态。
(2)静息时中度和重度狭窄组缺血节段各灌注参数较对照组降低,负荷后各狭窄组均较对照组降低,差异有统计学意义(p<0.05,0.01)。静息时重度狭窄组非缺血节段之前壁和下壁A×β值较其余三组升高,差异有统计学意义(p<0.05);负荷后重度狭窄组前壁A×β值、中度狭窄组前壁和下壁A×β值较对照组降低,差异有统计学意义(P<0.05,0.01)。
(3)灌注储备值比较:轻度狭窄组缺血节段A×β储备值、中度狭窄组β储备值及A×β储备值、重度狭窄组各储备值较对照组降低,差异有统计学意义(p<0.01)。重度狭窄组前壁β储备值和A×β储备值、下壁A×β储备值较对照组降低,差异有统计学意义(P<0.05)。
(4)静息及负荷状态下RT-MCE所测各组各节段血流量(A×β)与SPECT所测放射性计数相关性好(P<0.05,0.01)。
4.二维应变与扭转运动分析
(1)径向应变为正向波形,环向应变为负向波形,随狭窄程度增加径向应变峰值(RS)、环向应变峰值(CS)呈逐渐降低趋势。
缺血节段比较:重度狭窄组各平面侧壁和后壁RS和CS较对照组和轻度狭窄组降低,中度狭窄组各平面侧壁和后壁RS和CS较对照组降低,差异有统计学意义(p<0.05,0.01)。
非缺血节段比较:重度狭窄组各平面前壁RS和CS、二尖瓣及乳头肌平面下壁RS较对照组降低,中度狭窄组乳头肌平面前壁和下壁RS较对照组降低,差异有统计学意义(p<0.05,0.01)。
(2)对照组心尖及二尖瓣平面各节段旋转曲线形态较为一致,即心尖平面呈逆时针方向旋转,旋转角度(Rot)为正值;二尖瓣平面为顺时针方向旋转,Rot为负值。各狭窄组心尖及二尖瓣平面旋转方向与对照组基本一致。
缺血节段比较:与对照组比较,重度狭窄组各平面、中度狭窄组二尖瓣和乳头肌平面、轻度狭窄组二尖瓣平面侧壁和后壁Rot降低,差异有统计学意义(p<0.05,0.01)。中度和重度狭窄组各平面侧壁和后壁Rot较轻度狭窄组降低,差异有统计学意义(p<0.05,0.01)。
非缺血节段:中度和重度狭窄组二尖瓣平面前壁、重度狭窄组乳头肌平面前壁Rot较对照组降低,差异有统计学意义(p<0.05)。
(3)左室扭转角度(心尖与二尖瓣平面收缩期峰值旋转角度之差值)比较:中度和重度狭窄组侧壁和后壁之扭转角度较对照组和轻度狭窄组降低,差异有统计学意义(p<0.05)。重度狭窄组前壁扭转角度较对照组降低,差异有统计学意义(p<0.05)。
结论
1.开胸法于家猪冠状动脉左旋支近端置入Ameroid缩窄环,经冠状动脉造影证实可成功制备慢性心肌缺血模型,方法可靠。
2.定量分析表明,随狭窄程度逐渐增加,缺血节段射血分数和定量灌注参数呈逐渐降低趋势。中度和重度狭窄组与对照组比较,差异有统计学意义。
3.RT-MCE所测血流量与SPECT所测放射性计数相关性好。冠状动脉在正常状态下具有良好的储备能力。轻、中度狭窄组缺血节段心肌仍存在储备能力,但储备值分析发现,其储备能力较正常组降低。重度狭窄组缺血节段收缩功能及灌注指标降低、储备能力丧失,非缺血节段储备值也降低。
4.实时三维超声心动图通过定量分析左室多个节段间达最小容积时间之最大差值、标准差及其标化值,可评价左室内机械不同步性,标化值较绝对值能更敏感地发现收缩不同步。
5.随狭窄程度进行性增加,缺血节段径向及环向应变、旋转角度均呈逐渐降低趋势,中、重度狭窄组缺血区多数节段应变及旋转角度较对照组降低。
6.超声斑点追踪成像、实时三维超声心动图、实时心肌声学造影从不同方面反映心肌缺血后左室各节段心肌的运动及微循环灌注的变化,联合应用负荷试验可评价静息及负荷状态下的运动及微循环灌注改变及其储备,显示静息状态未显示的一些异常,提高诊断敏感性。
Backgrounds and Objectives
Ischemic heart disease is one kind of the most common heart diseases and coronary artery stenosis is the most common cause, which is called coronary artery disease (CAD). Chronic ischemia is more often occurred than the acute in clinical. Left ventricular (LV) systolic function is important in the diagnosis of CAD, and is related to the severity and range of myocardial ischemia and to effective blood perfusion. However, in the early phase of myocardial ischemia, when the regional wall motion has been changed, the global function may be still in the normal range owing to the compensation of the segment near to the ischemic territory and would be mistaken to normal. So the quantitative assessment of regional myocardial wall motion and blood perfusion plays important role in the diagnosis of CAD. Recent updates in the field of echocardiography have resulted in improvements in both image quality and techniques permitting simultaneous assessment of global and regional myocardial structure, function, and perfusion, enabling non-invasive assessment of coronary artery disease.
When echocardiography quantifying LV systolic function, LV ejection fraction (EF) is the most commonly used index. Two-dimensional echocardiography (2DE) is the most common technique, but it has pitfalls when LV morphology changed obviously. Recently, real-time three-dimensional echocardiography (RT-3DE) could acquire full volume data within only several seconds, enabling truly real time three dimensional data acquisition. And full volume data could be obtained with probe located at apical region, avoiding measurement error coming from the change of probe location and the different cardiac cycle. Further more, RT-3DE displays directly LV three dimensional morphology and then calculate LV volume directly, need no geometry hypothesis, as is in the 2-DE, so it conquer the limitation of 2-DE. RT-3DE analyzes all segmental volumes during the same cardiac cycle, and calculates segmental EF (SEF) from segmental volume of end diastole and end systole.
Rhythmic LV contraction and relaxation is necessary to maintain normal cardiac function. Cardiac resynchronization therapy has been proved effective in improving cardiac function of the patients of LV contractile dyssynchrony. But the problem is how to determine LV contractile dyssynchrony. RT-3DE outline LV endocardium and display directly the 3-dimensional morphology, reflect accurate LV volume change during cardiac cycle, so has potential superiority in evaluating LV synchronization.
More recently, speckle tracking echocardiography, a new echocardiographic 2-dimensional (2D) strain technique based on automatic tracking the two-dimensional motion of characteristic speckle patterns in B-mode images, enables simultaneous valuation of regional myocardial strain in both the radial and circumferential directions (i.e., circumferential strain (CS), and radial strain (RS) ) from parasternal short-axis view. Two-dimensional strain is in principle angle independent, and has been shown to be repeatable and reproducible, and accurate and correlate well with sonomicrometry and magnetic resonance imaging tagging during ischemia.
Normal LV myocardial contractility depends on sufficient blood perfusion. Ischemia leads to abnormal myocardial metabolism and then to abnormal myocardial contractility in CAD. Real-time myocardial contrast echocardiography (RT-MCE) is a newly developed technique to quantify myocardial blood perfusion, displaying the replenishment process of microbubbles into myocardium after microbubbles being destroyed by a high energy pulse. The replenishment of contrast can be characterized by a time-intensity curve (i.e. destruction–refilling curve), which can be fitted to a monoexponential function: y=A×(1-eβt)+C. The plateau value (A) of the replenishment curve reflects the myocardial blood volume, and the slope (β) reflects the reappearance rate of microbubbles (i.e. myocardial microbubble velocity). The product of A×βtherefore represents myocardial blood flow. Thus RT-MCE could analyze quantitively the microvascular blood perfusion in regions of interest in myocardium with specialist software.
Conronary artery has powerful compensation capacity, so mild to moderate stenosed coronary vessel will supply adequate blood to maintain normal function at rest, so echocardigraphy may display no abnormality in LV wall motion and perfusion. Stress will induce an increase of myocardial consumption of oxygen, but in stenosed artery the blood supply could not increase accordingly, leading to ischemia in the victim territory, therefore abnormal wall motion and perfuison will be found in echocardiography. Dobutaming stress echocardiography (DSE) is one of the favorite stress methods, and is often applied to 2DE, RT-3DE or RT-MCE and combined with baseline, to evaluate the myocardial motion or blood perfusion in both stress and rest condition and further to evaluate the reserves, thus increases the technique's sensitivity and accuracy, and has potential to anticipate prognosis.
In the present study, chronic myocardial ischemia was induced by placing an Ameroid constrictor in the left circumflex in swines, then RT-3DE and RT-MCE examination combining rest and DSE was performed to ascertain chronic ischaemic LV dysfunction and myocardial perfusion and reserves, and Vivid 7 was used to assess 2 dimensional strain and torsional anomalies, so as to validate the role of Echocardiography to recognize regional contractile variations and perfusional anomalies for the detection of ischemia.
Methods
A chronic ischemic model was induced and echocardiography and coronary angiography was performed as described below before LCX constriction, every week after LCX constriction, until the LCX stenosis was of≥90% validated coronary angiographically. Then animals were killed, hearts were harvested and processed for hematoxylin and eosin (HE) stain, Poley stain and scanning electron microscopy.
Chronic ischemic model and Animal preparation
Ten normal juvenile domestic swines in either gender, body weight 20 to 26Kg, were subjected to induce chronic ischemia by constricting the left circumflex artery (LCX) with Ameroid constrictor. Pigs were sedated with an intramuscular injection of 300mg ketamine (about 15mg/Kg) with 5mg midazolam and 1mg atropine, intubated, and maintained with combined anesthesia with inhalant enflurane and intravenous vecuronium bromide. A thoracotomy was performed through the fourth left intercostal space. The pericardium was opened and an Ameroid constrictor was placed around the proximal LCX just distal to the main stem of the left coronary artery. The chest was then closed, and the animals were allowed to recover and returned to their cages. This animal experiment was approved by the Animal Care Committee of Third Military Medical University.
RT-3DE and RT-MCE Echocardiographic data acquisition
General anesthesia was initiated with ketamine (15mg/Kg) with 1mg atropine intramuscular, and maintained with intravenous ketamine or intraperitoneal pentobarbital. Animals were investigated in the closed-chest state in the left lateral decubitus position. All RT-3DE Full Volume echocardiograms were obtained with iE33 ultrasound machine (Philips Medical Systems) with Probe X3-1, with Probe located at apical area. If the border was unclear, ZhiFuXian—a homemade contrast agent in our laboratory was infused to enhance the resolution. RT-MCE contrast images of parasternal short axis at PM level were acquired with iE33 machine, S5 probe. The LVO pattern was select and set as second harmonic (transmit/receive: 1.7/3.4 MHz), mechanic index 0.1, beats 20.
Images were copied to QLAB 5.2 postprocess workstation, and 3DQ and 3DQA software was used to analyze Full Volume data sets, and LV global ejection fraction (EF) and EDV and ESV of 16 segments except for apex were yielded, and then segmental EF (SEF) were calculated with EXCEL. Software 3DQA provided the maxium difference of Tmsv (Tmsv-dif) and standard deviation (Tmsv-SD) among various segments and standard index (Tmsv-dif% and Tmsv-SD%), to evaluate LV dyssynchrony. ROI software were used to analyze contrast images, and yielded the plateau value A of the replenishment curve (A reflects the myocardial blood volume), the slopeβ(βreflects the myocardial velocity). Calculate the product of A×β( A×βrepresents myocardial blood flow).
DSE images acquisition and data analysis
After the RT-3DE and RT-MCE images were acquired, dobutamine was administered intravenous by micro-infusion pump according to the low-dose protocol (5μg/kg/min followed by 10μg/kg/min, each step lasting 5 min). When target heart rate increased to 20bpm higher than that of baseline, repeated the baseline image acquisition. The reserve was determined as the ratio of the data of stress to that of the baseline, including SEF reserve, A reserve,βreserve, and A×βreserve, reflecting the contractile and perfusion reserve function. Each data was an average of two measurements.
Two-dimensional Strain imaging and data analysis
Animals anesthesia and prepare as before. A Vivid 7 (GE Medical Systems) was used to acquire 2D strain images data with a M3S Probe. B-mode second harmonic images (frame rate≥50 frames/s) were recorded in parasternal apical, middle and basal short axis views of three consecutive cardiac cycles. The digital data were stored and transferred to a computer for subsequent offline analyses.
Digital data were transferred to a dedicated software EchoPac (GE Medical Systems) for subsequent offline analysis. Each level of LV was divided into six segments, and each segment was individually analyzed. Two-dimensional peak radial and circumferential strains during systole were measured. By tracing the endocardial contour on an end-diastolic frame, the software will automatically track the contour on subsequent frames. Adequate tracking can be verified in real-time and corrected by adjusting the region of interest semi-manually to ensure optimal tracking. Circumferential strain (CS) and radial strain (RS) were recorded. At the same time, left ventricular rotation at apical and basal level of each wall and LV torsion were analyzed. The rotation difference between apical level and mitral level reflected the LV torsional angle (Tor).
Selective coronary angiography
Selective coronary angiography was performed the same day as or the day after the echocardiography to confirm the stenosis degree of LCX. Quantitative coronary angiography was performed through cine review by two blinded experienced angiographers. The stenosis at site of Ameroid placement was calculated by the following equation: (1 ? lumen diameter stenotic site/lumen diameter reference)×100. The severity of LCX stenosis were grouped into mild stenosis (stenosis <50%), moderate stenosis (stenosis 50~75%) and severe stenosis (stenosis≥75%).
Gated SPECT myocardium perfusion imaging and data analysis
99mTc-MIBI Gated SPECT myocardium perfusion imaging was performed with Infinia Hawkeye SPECT instrument (GE Medical Systems) 1 to 3 day after Echocardiogram. Two day method was used to perform rest/stress scan, with scanning at rest performed 90 min after intravenous infusion 15mCi 99mTc-MIBI on first day, then scanning the same way at stress on the second day.
Emory Cardiac Toolbox for cardiac was used to analyze the Dicom data. LV functional parameters and LV mass was yielded. Region of interest was set at the center of 6 segments at LV short axis corresponding to echogram, radioactive counting was then measured. Statistical analysis
Data were expressed as mean±SD. Statistical analysis was performed with SPSS 13.0 software. Measurements values were grouped by the severity of LCX stenosis verified by selective coronary angiography and their means were compared. Measurements of at rest and stress were compared by a paired Student t test. Multiple comparisons between different groups were performed using ONE-WAY ANOVA analysis followed by post-hoc least-significant difference test. A p<0.05 was considered statistically significant for all analysis.
Results
Animal models and animal group
Of the 10 subjects, 8 were induced chronic ischemia successfully and each was showed severe stenosis of LCX 4 to 6 weeks after placement of an Ameroid constrictor verified by quantitative coronary angiography analysis. Total times of echocardiography examination of all the 8 pigs from 1 to 6 weeks post operation were 38, of which 3 were excluded owing to unclear images, and 35 times were included in analysis, of which mild, moderate and severe stenosis were 12, 12 and 11 times respectively, according to the coronary angiography. Ten normal pigs before operation served as controls.
RT-3DE variables
Compared with baseline, the global ejection fraction (EF) and segmental ejection fraction (SEF) of most segments in severe stenosis decreased in stress condition, while that in control, mild and moderate stenosis increased (p<0.05, 0.01).
LV SEF showed a tendency of gradually decrease according to the progressive LCX stenosis under both baseline and stress condition.
SEF of LCX territory region compare among groups: under both baseline and stress condition, SEF of lateral and posterior wall at mitral and papillary muscle (PM) level decreased significantly in moderate and severe stenosis, compared with control and mild stenosis. At stress, SEF of lateral and inferior wall at apical level in severe stenosis and SEF of lateral and posterior wall at mitral level in mild stenosis decreased, compared with control. (p<0.05, 0.01).
SEF of LAD and RCA territory region compare among groups: SEF of anterior and inferior wall at mitral and PM level decreased significantly in severe stenosis at stress, compared with control. (p<0.05).
SEF reserve compare among groups: SEF reserve had a tendency of gradually decrease along with the progress of LCX stenosis. SEF reserve of lateral and posterior wall at all levels decreased significantly in moderate and severe stenosis, compared with control. Among the LAD and RCA segments, anterior and inferior wall at mitral and PM level and inferior wall at apical level showed marked decrease of SEF reserve in severe stenosis, compared with control (p<0.05, 0.01).
Synchrony evaluation: RT-3DE analyzed quantitively the maximum difference and standard deviation of time to minimal segmental volume (Tmsv) among segments. The results indicated that RT-3DE in healthy controls showed highly synchronous contraction in contrast to widespread dyssynchrony found in subjects of moderate and severe stenosis, and dyssynchrony found only in basal segments in mild stenosis.
RT-MCE variables
Compared with baseline, A and A×βof lateral wall and posterior wall decreased obviously, andβand A×βof other segments increased under stress in severe stenosis (p<0.05,0.01). By contrast, all perfusion variables (A,βand A×β) of all segments in other groups increased (p<0.05, 0.01).
Perfusion parameters of LCX territory region compared among groups: all perfusion variables of lateral and posterior wall decreased significantly in moderate and severe stenosis at rest, compared with control. By contrast, those variables decreased in all stenosis groups at stress, and statistical difference was found among all stenosis groups. (p<0.05, 0.01).
Perfusion parameters of other segments compare among groups: at rest A×βof anterior and inferior wall in severe stenosis increased significantly, compared with other groups (p<0.05, 0.01). At stress A×βof anterior wall in severe stenosis and A×βof anterior and inferior wall in moderate stenosis decreased significantly, compared with control (p<0.05).
Perfusion reserve variables compare: A×βreserve of lateral and posterior wall in mild stenosis,βand A×βreserve in moderate stenosis and reserves of A,β, and A×βin severe stenosis decreased significantly, compared with control (p<0.05, 0.01). Of nonischemic segments, anterior wall demonstrated decreasedβand A×βreserve and inferior wall decreased A×βreserve in severe stenosis, compared with control (p<0.05).
Under both rest and stress condition, myocardial blood flow of all segments in each group measured by RT-MCE correlated well with radioactive counting by SPECT (all p<0.05, 0.01).
Two-dimensional Strain and torsion variables
1. The circumferential strain curve was positive wave form, and radial strain curve was negative. The peak value of the circumferential strain curve (CS) and radial strain curve (RS) had a tendency of gradually decrease according to the progressive stenosis. LCX segments compare among groups: RS and CS of lateral and posterior wall decreased significantly at all levels in severe stenosis, compared with control and mild stenosis; and decreased significantly at all levels in moderate stenosis, and at mitral level in mild stenosis, compared with control (p<0.05, 0.01).
LAD and RCA segments compare among groups: compared with control, RS and CS of anterior wall at all levels and RS of inferior wall at mitral and PM levels in severe stenosis decreased significantly, while RS of anterior and inferior wall at PM level in moderate stenosis decreased significantly (p<0.05, 0.01).
2. At apical and mitral level, rotation curve of each segment of LV had homogeneous wave form, i.e., LV rotated counterclockwise at apical level (positive angle) and rotated clockwise at mitral level (negative angle). LCX stenosis groups had almost the same rotation direction at both apical and mitral level like that of control.
LCX segments compare among groups: Rotation angle of lateral and posterior wall at all levels in severe stenosis, at mitral and PM level in moderate stenosis, and at mitral level in mild stenosis decreased significantly, compared with control (p<0.05, 0.01). Rotation angle of lateral and posterior wall at all levels in moderate and severe stenosis also decreased significantly, compared with mild stenosis (p<0.05,0.01).
Nonischemic segments compare among groups: Rotation angle of anterior wall at mitral level in moderate and severe stenosis and of anterior wall at PM level in severe stenosis decreased significantly, compared with control (p<0.05).
3. Torsional angle (Tor) compare: Torsional angle of lateral and posterior wall in moderate and severe stenosis decreased significantly, compared with control and mild stenosis (p<0.05). Compared with control, Tor of anterior wall in severe stenosis decreased significantly (p<0.05).
Conclusions
1. Chronic ischemia model induced by placing an Ameroid constrictor at the left circumflex artery (LCX) is angiographically documented.
2. Quantitative analysis indicates that along with progressive stenosis, segmental ejection fraction and perfusion parameters of ischemic segments decrease gradually. There is statistical difference of those parameters in moderate and severe stenosis compared with control.
3. A linear relationship exists between myocardial blood flow measured by RT-MCE and radioactive counting by SPECT. Normal coronary artery has sufficient reserve capacity. Although territories supplied by mild and moderate stenotic LCX still have some reserve ability, they are impaired according to reserve analysis. Segments supplied by severe stenotic LCX demonstrate decreased myocardial contractility and perfusion and exhausted reserve capacity, company by impaired reserve capacity of nonischemic regions.
4. RT-3DE could evaluate LV dyssynchrony by analyzing the maximum difference and standard deviation and standard variables of time to minimal segmental volume, and standard variable is found more sensitive than the absolute time value.
5. Along with progressive stenosis, circumferential strain, radial strain and rotation angle show progressive decrease tendency. Most segments of the victim regions in moderate and severe stenosis decrease markedly than that of control.
6. Real-time three-dimensional echocardiography, real-time myocardial contrast echocardiography and speckle tracking echocardiography reflect various aspects of LV segmental wall motion and microvascular perfusion. Combining assessment parameters at baseline and dobutaming stress, they could evaluate the myocardial motion or blood perfusion during both rest and stress condition and further to evaluate the reserves, finding indications concealed at sole rest, thus increases the techniques' diagnostic sensitivity.
引文
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