Contrast Ultrasound, Sonothrombolysis and Sonoperfusion in Cardiovascular Disease: Shifting to Theragnostic Clinical Trials

Abstract

Contrast ultrasound has a variety of applications in cardiovascular medicine, both in diagnosing cardiovascular disease as well as providing prognostic information. Visualization of intravascular contrast microbubbles is based on acoustic cavitation, the characteristic oscillation that results in changes in the reflected ultrasound waves. At high power, this acoustic response generates sufficient shear that is capable of enhancing endothelium-dependent perfusion in atherothrombotic cardiovascular disease (sonoperfusion). The oscillation and collapse of microbubbles in response to ultrasound also induces microstreaming and jetting that can fragment thrombus (sonothrombolysis). Several preclinical studies have focused on identifying optimal diagnostic ultrasound settings and treatment regimens. Clinical trials have been performed in acute myocardial infarction, stroke, and peripheral arterial disease often with improved outcome. In the coming years, results of ongoing clinical trials along with innovation and improvements in sonothrombolysis and sonoperfusion will determine whether this theragnostic technique will become a valuable addition to reperfusion therapy.

Keywords: cardiovascular; contrast ultrasound; sonoperfusion; sonothrombolysis; theragnostics.

Figure 1:. Diagnostic applications of contrast ultrasound

Left upper image: mural thrombus visible with contrast echocardiography. Right upper image: persistent apical perfusion defect after percutaneous coronary intervention for left anterior descending artery infarction. Left lower image: contrast ultrasound of the carotid artery demonstrating intraplaque neovascularization. Reprinted from Feinstein et al. (13) with permission from Elsevier. Right lower image: leakage of the endovascular graft undetected with angiography and unenhanced ultrasound, but visible with contrast ultrasound. Reprinted from Bianchini et al. (21) with permission from Elsevier.

Figure 2:. Color Doppler signal enhancement with MBs

A: No color Doppler signals detectable in unenhanced transcranial color-coded Doppler ultrasound. B: In contrast-enhanced TCCD examinations, the color-coded Doppler signals from the posterior cerebral artery (P) and anterior cerebral artery (A) are clearly visualized, while signals from the middle cerebral artery (M) is absent. C:Occlusion of the MCA was later confirmed on computed tomography angiography. Reprinted from Postert et al. (23) with permission from Wolters-Kluwer.

Figure 3.. Theragnostic ultrasound:

A: Occlusion of the proximal middle cerebral artery treated with tPA 2-MHz transcranial power Doppler ultrasound. At 120 minutes, spectral wave forms and power Doppler signals indicate complete recanalization with marked improvement in NIHSS score. Reprinted from: Alexandrov et al. (74) with permission of Massachusetts Medical Society B: Occlusion of the left anterior descending coronary artery with diagnostic guided intermittent high mechanical index ultrasound. Notice the microvascular defect at the apex before treatment (left) and reperfusion after treatment (right). Reprinted from Mathias et al. (92) with permission from Elsevier.

Central illustration:. Sonothrombolysis and sonoperfusion

Top: Schematic overview of the different mechanisms underlying tissue reperfusion in vascular ischemic disease. The two major components are sonothrombolysis as a result of erosive forces and shear-mediated release of vasodilators leading to increased microvascular blood flow. Arrow thickness refers to the relative contribution of the ultrasound bioeffects on sonothrombolysis and sonoperfusion. Bottom: Different factors affecting sonothrombolysis and sonoperfusion success. ATP: adenosine triphosphate, MI: mechanical index, t-PA: tissue plasminogen activator, US: ultrasound