Pulsed high-intensity-focused US and tissue plasminogen activator (TPA) versus TPA alone for thrombolysis of occluded bypass graft in swine

Abstract

Purpose: Prosthetic arteriovenous or arterial-arterial bypass grafts can thrombose and be resistant to revascularization. A thrombosed bypass graft model was created to evaluate the potential therapeutic enhancement and safety profile of pulsed high-intensity-focused ultrasound (pHIFU) on pharmaceutical thrombolysis.

Materials and methods: In swine, a right carotid-carotid expanded polytetrafluoroethylene bypass graft was surgically constructed, containing a 40% stenosis at its distal end to induce graft thrombosis. The revascularization procedure was performed 7 days after surgery. After model development and dose response experiments (n = 11), two cohorts were studied: pHIFU with tissue plasminogen activator (TPA; n = 4) and sham pHIFU with TPA (n = 3). The experiments were identical in both groups except no energy was delivered in the sham pHIFU group. Serial angiograms were obtained in all cases. The area of graft opacified by contrast medium on angiograms was quantified with digital image processing software. A blinded reviewer calculated the change in the graft area opacified by contrast medium and expressed it as a percentage, representing percentage of thrombolysis.

Results: Combining pHIFU with 0.5 mg of TPA resulted in a 52% ± 4% increase in thrombolysis on angiograms obtained at 30 minutes, compared with a 9% ± 14% increase with sham pHIFU and 0.5 mg TPA (P = .003). Histopathologic examination demonstrated no differences between the groups.

Conclusions: Thrombolysis of occluded bypass grafts was significantly increased when combining pHIFU and TPA versus sham pHIFU and TPA. These results suggest that application of pHIFU may augment thrombolysis with a reduced time and dose.

Figure 1

Multiplanar reformatted reconstruction of CT angiography images of the thrombosed graft demonstrate a 40% diameter stenosis near the distal anastomosis, which translates to 50%–60% area reduction of the lumen (measured on CT axial images; not shown).

Figure 2

Pretreatment and 30-minute posttreatment angiograms in the sham pHIFU group (upper row) and pHIFU group (lower row). The clamps delineate the extremities of the graft per CT imaging. The infusion segment of the lysis catheter (between the two radiopaque markers) is positioned within the graft. A pretreatment angiogram confirms graft thrombosis. Not much improvement is seen in the sham group (top row), as opposed to a 50% recanalization of the graft in the pHIFU group (bottom row). Also shown is the Livewire tracing of the contrast area on the 30-minute angiogram.

Figure 3

Percentage of thrombolysis. The graft dimensions (width and length) were used to calculate the graft area in image space (adjusted for magnification). The area of the graft opacified by contrast agent was traced on the angiograms at each time point. That area was divided by the graft area to give the percentage of patent graft area at each time point. The difference in percentage of patent graft area at each time point compared with the pretreatment angiogram represents the percentage of thrombolysis and is demonstrated with the SD at each time point.

Figure 4

Hematoxylin and eosin-stained pathologic sections containing graft from an animal treated with pHIFU and TPA (a) or sham pHIFU and TPA (b). The slides demonstrate the grafts surrounded by reactive fibrovascular tissue and fluid accumulation most likely related to postoperative changes. Similar findings are seen in both slides. No additional findings are seen in the pHIFU-treated animal. (Original magnification, × 5.)

Figure 5

Hematoxylin and eosin–stained pathologic section from animals treated with pHIFU and TPA (a) or sham pHIFU and TPA (b). The slides demonstrate that the graft walls are infiltrated with erythrocytes and fluid. This was similar in both groups in all specimens examined. (Original magnification, × 20.)