OBJECTIVES The authors investigated ideal acoustic conditions on a clinical scanner custom-programmed for ultrasound (US) cavitation-mediated flow augmentation in preclinical models. We then applied these conditions in a first-in-human study to test the hypothesis that contrast US can increase limb perfusion in normal subjects and patients with peripheral artery disease (PAD). BACKGROUND US-induced cavitation of microbubble contrast agents augments tissue perfusion by convective shear and secondary purinergic signalling that mediates release of endogenous vasodilators. METHODS In mice, unilateral exposure of the proximal hindlimb to therapeutic US (1.3 MHz, mechanical index 1.3) was performed for 10 min after intravenous injection of lipid microbubbles. US varied according to line density (17, 37, 65 lines) and pulse duration. Microvascular perfusion was evaluated by US perfusion imaging, and in vivo adenosine triphosphate (ATP) release was assessed using in vivo optical imaging. Optimal parameters were then used in healthy volunteers and patients with PAD where calf US alone or in combination with intravenous microbubble contrast infusion was performed for 10 min. RESULTS In mice, flow was augmented in the US-exposed limb for all acoustic conditions. Only at the lowest line density was there a stepwise increase in perfusion for longer (40-cycle) versus shorter (5-cycle) pulse duration. For higher line densities, blood flow consistently increased by 3-fold to 4-fold in the US-exposed limb irrespective of pulse duration. High line density and long pulse duration resulted in the greatest release of ATP in the cavitation zone. Application of these optimized conditions in humans together with intravenous contrast increased calf muscle blood flow by >2-fold in both healthy subjects and patients with PAD, whereas US alone had no effect. CONCLUSIONS US of microbubbles when using optimized acoustic environments can increase perfusion in limb skeletal muscle, raising the possibility of a therapy for patients with PAD. (Augmentation of Limb Perfusion With Contrast Ultrasound; NCT03195556).

中文翻译：

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微泡空化增强外周动脉疾病患者的组织灌注。

目的作者研究了在临床前模型中为超声（美国）气蚀介导的血流增强而定制编程的临床扫描仪上的理想声学条件。然后，我们在一项首次人体研究中应用了这些条件，以检验对比US可以增加正常受试者和外周动脉疾病（PAD）患者的肢体灌注的假说。背景技术US诱导的微泡造影剂的空化通过对流剪切和介导内源性血管舒张剂释放的继发性嘌呤能信号传导来增加组织灌注。方法在小鼠中，静脉注射脂质微泡后，将近端后肢单侧暴露于治疗性US（1.3 MHz，机械指数1.3），持续10分钟。US根据线密度（17、37、65条线）和脉冲持续时间而变化。通过US灌注成像评估微血管灌注，并使用体内光学成像评估体内三磷酸腺苷（ATP）释放。然后将最佳参数用于健康志愿者和PAD患者，其中小牛US单独或与静脉微泡造影剂输注相结合进行10分钟。结果在小鼠中，在所有声学条件下，暴露于美国的肢体血流量都增加了。只有在最低的线密度下，较长（40个周期）的脉冲持续时间与较短（5个周期）的脉冲持续时间才会逐步增加灌注。对于更高的线密度，在美国暴露的肢体中，血流始终增加3倍至4倍，而与脉搏持续时间无关。高线密度和长脉冲持续时间导致空化区域中最大的ATP释放。在人体中应用这些优化的条件以及静脉内造影剂，在健康受试者和PAD患者中，小腿肌肉的血流量均增加了2倍以上，而仅US治疗没有效果。结论当使用优化的声学环境时，微泡的使用可以增加肢体骨骼肌的灌注，从而增加了对PAD患者进行治疗的可能性。（使用对比超声增强肢体灌注； NCT03195556）。