Coronary and Microvascular Thrombolysis with Guided Diagnostic Ultrasound and Microbubbles in Acute ST Segment Elevation Myocardial Infarction

Xie, Feng; Slikkerveer, Jeroen; Gao, Shunji; Lof, John; Kamp, Otto; Unger, Evan C.; Radio, Stanley J.; Matsunaga, Terry O.; Porter, Thomas R.

doi:10.1016/j.echo.2011.09.007

Cited by 56 publications

(36 citation statements)

References 22 publications

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“…8,42 For limb perfusion, pre-clinical studies have demonstrated that addition of microbubbles to ultrasound alone results in a >5-fold greater effect on muscle blood flow and a greater increase in arterial dilation. 8 The effects of CEU on perfusion are greatest when the acoustic power is high enough to produce inertial cavitation (exaggerated microbubble oscillation and destruction), and there is also sufficient time between ultrasound exposures to allow refill of microbubbles into the ultrasound sector.…”

Section: Discussionmentioning

confidence: 99%

Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling

et al. 2017

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Background Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signalling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. Methods Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for ten minutes after intravenous injection of 2×108 lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signalling pathways were assessed by studying interventions that either (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or KATP channels; or (3) inhibited downstream signalling pathways involving endothelial nitric oxide synthase (eNOS) or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease (SCD). Results Therapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hrs in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with SCD. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced a nearly 40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or through adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of eNOS abolished the effects of therapeutic ultrasound, indicating downstream signalling through both NO and prostaglandins. Conclusions Therapeutic ultrasound using microbubble cavitation to increase muscle perfusion relies on shear-dependent increases in ATP which can act through a diverse portfolio of purinergic signalling pathways. These events can reverse hindlimb ischemia in mice for >24 hours, and increase muscle blood flow in patients with sickle cell disease. Clinical Trial Registration NCT01566890 (https://clinicaltrials.gov/ct2/show/NCT01566890)

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Section: Discussionmentioning

confidence: 99%

Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling

et al. 2017

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“…8,12 High-power ultrasound with MBs has been shown to augment capillary perfusion on intravital microscopy and to reduce ischemic damage in a porcine model of acute myocardial infarction presumably through effects on myocardial blood flow. 13–15 In this study we sought to quantify the degree to which ultrasound’s effects on vascular tone and tissue perfusion in normal and ischemic tissues are influenced by the presence of MBs. We also sought to characterize the biologic mediators responsible for increased perfusion during MB insonification by examining an array of compounds that can mediate vasodilation in response to vascular shear and/or pressure such as adenosine and the epoxyeicosatrienoic acid (EET) family of endothelial hyperpolarizing factors formed from cytochrome P450 metabolism of arachadonic acid.…”

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confidence: 99%

Augmentation of Limb Perfusion and Reversal of Tissue Ischemia Produced by Ultrasound-Mediated Microbubble Cavitation

Belcik

Mott

Xie

et al. 2015

Circ: Cardiovascular Imaging

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Background Ultrasound can increase tissue blood flow in part through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation, and sought to characterize the biologic mediators. Methods and Results Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in non-ischemic mice after unilateral 10 min exposure to intermittent ultrasound alone (mechanical index [MI] 0.6 or 1.3) or ultrasound with lipid microbubbles (2×108 I.V.). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (p<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3-fold and 10-fold higher than control for MI 0.6 and 1.3, respectively; p<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase (eNOS) attenuated flow augmentation produced by ultrasound and microbubbles by 70% (p<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide (NO) production and muscle phospho-eNOS increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40–50% reduction in flow), ultrasound (MI 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control non-ischemic limb. Conclusions Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of eNOS.

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“…Multiple animal studies have demonstrated that ultrasound in combination with microbubbles can recanalize acute intravascular thrombi in large vessels, including the iliofemoral arteries, 18,19 arteriovenous grafts, 20,21 central venous catheters, 22 coronary arteries, 23 and intracranial arteries, 24,25 underlining the potential of the treatment for dissolving microvascular thrombi. However, data on the effects of ultrasound and microbubble (US+MB) treatment on the thrombolysis of microthrombi are lacking, and it is unclear whether US+MB treatment may improve the outcomes of acute ischemic stroke induced by cerebral microthrombi.…”

mentioning

confidence: 99%

Microbubble-Mediated Sonothrombolysis Improves Outcome After Thrombotic Microembolism-Induced Acute Ischemic Stroke

Wang

Huang

et al. 2016

Stroke

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Microbubble-mediated sonothrombolysis is a promising treatment for cerebral microthrombi and is based on ultrasound driven cavitation of microbubbles that accelerate thrombolysis via localized mechanical stress on the thrombi. 17Background and Purpose-Microthrombi originating from disintegrated clots or formed in situ may account for the poor clinical improvement of acute ischemic stroke after recanalization therapy. We attempted to determine whether microbubble-mediated sonothrombolysis could dissolve platelet-rich and erythrocyte-rich microthrombi, thereby reducing their brain injury-causing potential. Methods-Platelet-and erythrocyte-rich microthrombosis were induced by periadventitial application of 5% ferric chloride or thrombin to mesenteric microvessels in 75 Sprague-Dawley rats. Acute ischemic stroke was induced by intracarotid injection of platelet-or erythrocyte-rich microthrombi in another 50 rats. Rats were randomly divided into control (CON), ultrasound (US), ultrasound and microbubble (US+MB), recombinant tissue-type plasminogen activator (r-tPA), and US+MB+r-tPA groups. The post-treatment mesenteric microvessel recanalization rates, cerebral infarct volumes, and neurological scores were determined. Results-The recanalization rates of platelet-and erythrocyte-rich microthrombi in mesenteric microvessels were higher (P<0.05), and the cerebral infarct volumes and neurological scores of rats with either microthrombi were lower in the US+MB group than in the CON group (P<0.01). The infarct volumes and neurological scores were greater in the r-tPA group than in the US+MB and US+MB+r-tPA groups after treatment of rats with platelet-rich microthrombi (P<0.05).In contrast, after treatment of rats with erythrocyte-rich microthrombi, the infarct volumes and neurological scores were similar in the r-tPA and US+MB groups, but smaller in the US+MB+r-tPA group (P<0.05). Conclusions-Microbubble-mediated sonothrombolysis improved the outcomes of microthrombi-induced acute ischemic stroke. Thus, this method may serve as an attractive adjunct to recanalization therapy for acute ischemic stroke.

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Coronary and Microvascular Thrombolysis with Guided Diagnostic Ultrasound and Microbubbles in Acute ST Segment Elevation Myocardial Infarction

Cited by 56 publications

References 22 publications

Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling

Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling

Augmentation of Limb Perfusion and Reversal of Tissue Ischemia Produced by Ultrasound-Mediated Microbubble Cavitation

Microbubble-Mediated Sonothrombolysis Improves Outcome After Thrombotic Microembolism-Induced Acute Ischemic Stroke

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