From the Bracco Suisse SA, Geneva, Switzerland.
Invest Radiol. 2014 Apr;49(4):224-35. doi: 10.1097/RLI.0000000000000018.
The diagnosis of acute coronary syndrome remains challenging especially in patients without clear symptoms or electrocardiographic and/or biomarker features. A hallmark of ischemia/reperfusion is activation of endothelial cells leading to altered expression of molecular markers, including selectins. In this context, we aimed to validate the value of ultrasound molecular imaging for detecting transient myocardial ischemia by using a clinically translatable dual P- and E-selectin-targeted ultrasound contrast agent (UCA) and microbubble (MB(selectin)).
Transient (20 minutes) myocardial ischemia of rat heart was produced by ligation of the left anterior descending coronary artery ligation followed by 2-, 5-, or 24-hour reperfusion. Imaging of the transient ischemic event was achieved by the use of MB(selectin). Performance of this clinically translatable targeted UCA was compared with that of antibody-targeted streptavidin MBs. Finally, immunohistochemistry staining of rat myocardial ischemic tissue was performed to assess expression of selectins accessible to targeted UCA.
In rats subjected to myocardial ischemia (20 minutes) followed by reperfusion (2 hours), injection of MB(selectin) produced high late phase (ie, 10-minute postinjection) ultrasound molecular imaging enhancement in the myocardium, which colocalized with the ischemic area. Late phase enhancement persisted 5 and 24 hours after reperfusion. Similarly, the use of MBP and MBE, comprising antibodies specific for P- and E-selectin, respectively, showed high late-phase enhancement within the ischemic area compared with remote myocardial tissue. Two and 5 hours after ischemia has resolved, a persistent expression of these 2 selectins was detected. After 24 hours of reperfusion, only MBE produced late phase enhancement within the ischemic myocardium. Immunohistochemical findings revealed that both P- and E-selectin were expressed and accessible on the surface of the activated endothelium 2 and 5 hours after the acute ischemic event, whereas only E-selectin remained accessible after 24 hours.
Ultrasound molecular imaging of transient myocardial ischemia using dual selectin-targeted UCA is able to monitor the time course of expression of selectins after resolution of the ischemic event, paving the way for a large clinical diagnostic window.
急性冠状动脉综合征的诊断仍然具有挑战性，特别是在没有明确症状或心电图和/或生物标志物特征的患者中。缺血/再灌注的一个标志是内皮细胞的激活，导致包括选择素在内的分子标志物的表达改变。在这种情况下，我们旨在通过使用一种临床可转化的双 P-和 E-选择素靶向超声对比剂（UCA）和微泡（MB（selectin））来验证超声分子成像检测短暂性心肌缺血的价值。
通过结扎左前降支冠状动脉结扎，随后再灌注 2、5 或 24 小时，产生大鼠心脏短暂（20 分钟）心肌缺血。使用 MB（selectin）实现短暂性缺血事件的成像。将这种临床可转化的靶向 UCA 的性能与抗体靶向链霉亲和素 MBs 的性能进行比较。最后，对大鼠心肌缺血组织进行免疫组织化学染色，以评估可被靶向 UCA 检测到的选择素的表达。
在经历心肌缺血（20 分钟）后再灌注（2 小时）的大鼠中，注射 MB（selectin）在心肌中产生高后期（即注射后 10 分钟）超声分子成像增强，该增强与缺血区域共定位。再灌注后 5 小时和 24 小时仍存在后期增强。同样，使用包含针对 P-和 E-选择素的特异性抗体的 MBP 和 MBE，与远程心肌组织相比，在缺血区域显示出高后期增强。在缺血消退后 2 小时和 5 小时，检测到这些 2 种选择素持续表达。在再灌注 24 小时后，只有 MBE 在缺血心肌中产生后期增强。免疫组织化学结果显示，在急性缺血事件后 2 小时和 5 小时，P-和 E-选择素均表达并可在激活的内皮细胞表面检测到，而只有 E-选择素在 24 小时后仍可检测到。
使用双选择素靶向 UCA 进行短暂性心肌缺血的超声分子成像能够监测缺血事件解决后选择素表达的时间过程，为大型临床诊断窗口铺平道路。
