Abstract 12635: Successful Microbubble Sonothrombolysis Without Tissue Plasminogen Activator in a Rabbit Model of Acute Ischemic Stroke
Introduction: Microbubbles (MB) combined with ultrasound (US) have been shown to enhance clot lysis without exogenous tissue plasminogen activator (tPA) in vitro and in dog and pig models. Using a rabbit model of acute ischemic stroke, we evaluate sonothrombolysis with 3 types of MB.
Hypothesis: Sonothrombolysis with MB alone is effective at decreasing infarct volumes.
Methods: New Zealand White rabbits (n = 74; 5.3 ± 0.04 kg) received angiography and a single 0.6 × 4.0 mm clot was injected into the internal carotid artery occluding its branches. Emboli were prepared by placing rabbit blood into plain 1.5 mm diameter blood collection tubes and clotting for 6 hours at 37°C, then cooling at 4°C for 72 hours. Rabbits were randomly assigned to one of six groups. Control (n = 11) rabbits were embolized but received no US, tPA, or MB. Other groups were tPA without US (n = 20), tPA+US (n = 10), Definity MB+US (n = 16), 3μm MB+US (n = 8), and platelet-fibrin-targeted 3μm MB+US (n = 9). Treatment was initiated one hour following angiographic verification of occlusion. Rabbits with US received pulsed wave US (1 MHz; 0.8 W/cm2) for 1 hour and rabbits with tPA received intravenous tPA (0.9 mg/kg) over 1 hour. Rabbits receiving Definity MB got intravenous MB (0.16 mg/kg) over 30 minutes. Rabbits given custom 3μm MB received 5 × 109 MB intravenously alone or tagged with a sub-therapeutic quantity of eptifibatide and antibody directed against fibrin over 30 minutes. Rabbits were sacrificed at 24 hours and infarct volume was determined using vital stains on brain sections.
Results: Infarct volume was lower for rabbits treated with Definity MB+US (1.0 ± 0.6% Definity MB+US vs control P = 0.013), 3μm MB+US (0.6 ± 0.9% 3μm MB+US vs control P = 0.018), and platelet-fibrin-targeted 3μm MB+US (0.8 ± 0.8% platelet-fibrin-targeted 3μm MB+US vs control P = 0.019) compared with control rabbits (3.5 ± 0.8%). The 3 MB types collectively differed (P = 0.004) from control. Infarct volume averaged 2.2 ± 0.6% and 1.7 ± 0.8% for rabbits treated with tPA alone and tPA+US, respectively. This was underpowered to show differences from control and MB groups.
Conclusions: Sonothrombolysis without tPA using either tagged or untagged MB is effective at decreasing infarct volumes. Study of human application is justified.
- © 2010 by American Heart Association, Inc.