Molecular Imaging of VWF (von Willebrand Factor) and Platelet Adhesion in Postischemic Impaired Microvascular Reflow

Abstract

Background: Complete mechanistic understanding of impaired microvascular reflow after MI will likely lead to new therapies for reducing infarct size. Myocardial contrast echocardiography (MCE) perfusion imaging and molecular imaging were used to evaluate the contribution of microvascular endothelial-associated Von Willebrand Factor (VWF) and platelet adhesion to microvascular “no-reflow”. Methods and Results: MI was produced by transient LAD ligation in wild-type mice, wild-type mice treated with rADAMTS13 (a proteolytic enzyme that regulates VWF), and ADAMTS13−/− mice. MCE perfusion imaging and molecular imaging of VWF and platelet GPIbα were performed 30 minutes after ischemia-reperfusion. Infarct size was measured at 3 days. Mortality during ischemia-reperfusion incrementally increased in wild-type+ADAMTS13, wild-type, and ADAMTS13−/− mice (14%, 43%, and 63%, respectively; p<0.05). For wild-type mice, molecular imaging signal for platelets and VWF in the post-ischemic risk area was 4–5-fold higher (p<0.05) compared to both the remote non-ischemic regions or to sham-treated mice. Signal enhancement in the risk area was completely abolished by ADAMTS13 treatment for both platelets (12.8±3.3 vs −1.0±4.4 IU, p<0.05) and VWF (13.9±4.0 vs −1.0±3.0 IU, p<0.05). ADAMTS13−/− compared with wild-type mice had 2–3-fold higher risk area signal for platelets (33.1±8.5 IU) and VWF (30.9±1.9 IU). Microvascular reflow in the risk area incrementally decreased for wild-type+ADAMTS13, wild-type, and ADAMTS13−/− mice (p<0.05), whereas infarct size incrementally increased (p<0.05). Conclusions: Mechanistic information on microvascular no-reflow is possible by combining perfusion and molecular imaging. In reperfused MI, excess endothelial-associated VWF and secondary platelet adhesion in the risk area microcirculation contribute to impaired reflow and are modifiable.

Seeing the Invisible—Ultrasound Molecular Imaging

“…The ability to image thrombus may also be important for monitoring the efficacy of antithrombotic therapies. It has been used in preclinical studies to evaluate new strategies aimed at inhibiting platelet-mediated thrombosis in atherosclerotic disease and in thrombotic complications of anti-cancer drugs (Moccetti et al 2018a(Moccetti et al , 2018bOzawa et al 2018;Latifi et al 2019). Finally, the targeting of MBs to a specific disease process could also be important in increasing their use in ultrasound-mediated therapy such as delivery of fibrinolytics or sonothrombolysis (Marsh et al 2007;Xie et al 2009;Kawata et al 2012).…”

“…More recently, these agents have been used not only to detect microvascular thrombosis in postinfarct microvascular no-reflow, but also to evaluate the role of new therapies for this condition (Fig. 4) (Ozawa et al 2018). They have also been used to detect renal platelet adhesion from VWF (Latifi et al 2019), giving hope that they could be eventually applied for more accurate diagnosis of thrombotic microangiopathies.…”

“…In this study, the degree of platelet adhesion was inversely correlated with adequacy of microvascular reflow. Reprinted with permission from Ozawa et al (2018). MB = microbubbles.…”

Ultrasound molecular imaging: insights into cardiovascular pathology

“…Recently, CEU molecular imaging with targeted MBs for platelet GPIbα and VWF have been applied to rapidly evaluate microvascular no-reflow phenomenon in rodent model of post-MI reperfusion, and the efficacy of new approaches to improving reflow. [39]. Additionally, CEU molecular imaging for platelet GPIbα and VWF have been developed to reveal a new form of vascular toxicity for the third-generation tyrosine kinase inhibitor ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produced ischemic wall motion abnormalities [30].…”

Assessing endothelium resistance to thrombus formation as a potential risk factor causing recurrent cardiovascular events in young patients after cardiac infarction

“…A. Sambola et al revealed a correlation between elevated von Willebrand factor concentration in blood plasma and thrombus resistance to fibrinolysis in patients with CI with ST elevation [38]. K. Ozawa et al, in their turn, revealed that an increase in endotheliumassociated von Willebrand factor concentration slowed down blood flow in the microcirculatory channel after CI [39]. Chinese researchers performed substantial meta-analysis aimed at estimating von Willebrand factor kinetics af-ter CI.…”