Abstract
It is estimated that only 2–6% of patients receive thrombolytic therapy for acute ischemic stroke suggesting that alternative therapies are necessary. In this study, we investigate the potential for high intensity focused ultrasound (HIFU) to initiate thrombolysis in an embolic model of stroke. Iron-loaded blood clots were injected into the middle cerebral artery (MCA) of New Zealand White rabbits, through the internal carotid artery and blockages were confirmed by angiography. MRI was used to localize the iron-loaded clot and target the HIFU beam for treatment. HIFU pulses (1.5 MHz, 1 ms bursts, 1 Hz pulse repetition frequency, 20 s duration) were applied to initiate thrombolysis. Repeat angiograms and histology were used to assess reperfusion and vessel damage. Using 275 W of acoustic power, there was no evidence of reperfusion in post-treatment angiograms of 3 rabbits tested. In a separate group of animals, 415 W of acoustic power was applied and reperfusion was observed in 2 of the 4 (50%) animals treated. In the last group of animals, acoustic power was further increased to 550 W, which led to the reperfusion in 5 of 7 (∼70%) animals tested. Histological analysis confirmed thatthe sonicated vessels remained intact after HIFU treatment. Hemorrhage was detected outside of the sonication site, likely due to the proximity of the target vessel with the base of the rabbit skull. These results demonstrate the feasibility of using HIFU, as a stand-alone method, to cause effective thrombolysis without immediate damage to the targeted vessels. HIFU, combined with imaging modalities used to identify and assess stroke patients, could dramatically reduce the time to achieve flow restoration in patients thereby significantly increasing the number of patients which benefit from thrombolysis treatments.
Highlights
IntroductionSystemic delivery of the thrombolytic agent tissue plasminogen activator (tPA), is the primary medical intervention for acute ischemic stroke. tPA is effective at restoring partial flow, depending on thrombus size and time to treatment, leading to approximately 30% improvement in symptoms at 3 months [1]
Systemic delivery of the thrombolytic agent tissue plasminogen activator, is the primary medical intervention for acute ischemic stroke. tPA is effective at restoring partial flow, depending on thrombus size and time to treatment, leading to approximately 30% improvement in symptoms at 3 months [1]
Our model of embolic stroke resulted in reproducible blockages in the proximal middle cerebral artery (MCA) as detected by C-arm angiography (Figure 2A,B) and confirmed by identification of the iron-loaded clot on Time of flight images (TOF)-MRI (Figure 2C)
Summary
Systemic delivery of the thrombolytic agent tissue plasminogen activator (tPA), is the primary medical intervention for acute ischemic stroke. tPA is effective at restoring partial flow, depending on thrombus size and time to treatment, leading to approximately 30% improvement in symptoms at 3 months [1]. TPA is effective at restoring partial flow, depending on thrombus size and time to treatment, leading to approximately 30% improvement in symptoms at 3 months [1]. Ultrasound is a technique which can improve clot lysis and reduce the amount of tPA required for effective treatment. It has been shown in vitro and in vivo that ultrasound enhances clot lysis in the presence of a thrombolytic agent compared to the agent alone [3,4]. Ultrasound has been combined with systemic delivery of microbubble contrast agents, which improves thrombolysis in the presence or absence of tPA [5,6,7,8]. Ultrasound, microbubbles and tPA together, improve recanalization and have no effect on the hemorrhage rates observed with tPA alone [9,10]
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