A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.

Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.

Background: Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI).

Methods: Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy.

Reduced Proteolytic Cleavage of von Willebrand Factor Leads to Aortic Valve Stenosis and Load-Dependent Ventricular Remodeling.

We hypothesized that excess endothelial-associated von Willebrand factor (vWF) and secondary platelet adhesion contribute to aortic valve stenosis (AS). We studied hyperlipidemic mice lacking ADAMTS13 ( ), which cleaves endothelial-associated vWF multimers. On echocardiography and molecular imaging, compared with control strains had increased aortic endothelial vWF and platelet adhesion and developed hemodynamically significant AS, arterial stiffening, high valvulo-aortic impedance, and secondary load-dependent reduction in LV systolic function.

Augmentation of Pulmonary Perfusion by Conducted Effects of a Pulmonary Artery Ultrasound Catheter.

Ultrasound (US) generated by catheters used clinically for US-facilitated thrombolysis can release shear-dependent vasodilators from endothelial and red blood cells. We hypothesized that catheter-based US in the pulmonary artery (PA) decreases downstream vascular resistance and increases pulmonary blood flow. In rhesus macaques, a U.

Treatment of Limb Ischemia with Conducted Effects of Catheter-Based Endovascular Ultrasound.

Ultrasound (US) is known to stimulate endogenous shear-dependent pathways, and can lower microvascular resistance through mediators that are conducted downstream from US exposure. We hypothesized that endovascular US, already in use for thrombolysis in humans, can improve tissue perfusion in the setting of acute limb ischemia through downstream-conducted effects. Models of severe peripheral arterial disease were developed in mice and in rhesus macaques.

Augmentation of Tissue Perfusion with Contrast Ultrasound: Influence of Three-Dimensional Beam Geometry and Conducted Vasodilation.

Background: Cavitation of microbubble contrast agents with ultrasound produces shear-mediated vasodilation and an increase in tissue perfusion. We investigated the influence of the size of the cavitation volume by comparing flow augmentation produced by two-dimensional (2D) versus three-dimensional (3D) therapeutic ultrasound. We also hypothesized that cavitation could augment flow beyond the ultrasound field through release of vasodilators that are carried downstream.

Echocardiographic Molecular Imaging of the Effect of Anticytokine Therapy for Atherosclerosis.

Background: Echocardiographic molecular imaging techniques are beginning to be applied to evaluate preclinical efficacy of new drugs. In a large clinical trial, anti-interleukin-1β (IL-1β) immunotherapy reduced atherosclerotic events, yet treatment effects were modest, and the mechanisms of action were not fully elucidated. We tested the hypothesis that echocardiographic molecular imaging can assess changes in vascular thromboinflammatory status in response to anti-IL-1β therapy.

Proteolysis of Von Willebrand Factor Influences Inflammatory Endothelial Activation and Vascular Compliance in Atherosclerosis.

This study used in vivo molecular imaging to characterize endotheliall activation attributable to von Willebrand factor (vWF)-mediated platelet adhesion in atherosclerosis. In atherosclerotic mice lacking the low-density lipoprotein receptor on Western diet, the additional genetic deletion of the ADAMTS13, which cleaves endothelial-associated vWF, produced greater aortic molecular imaging signal for not only vWF and platelets, but also for endothelial adhesion molecules VCAM1 and P-selectin, larger plaque size, and lower aortic distensibility. Sustained ADAMTS13 therapy reduced signal for all 4 molecular targets and plaque size.

Regional and Conducted Vascular Effects of Endovascular Ultrasound Catheters.

Intra-vascular ultrasound catheters are used clinically to facilitate clot lysis. We hypothesized that these devices could also directly lower microvascular resistance and increase tissue perfusion through established shear-dependent pathways. In mice, either the proximal hind-limb muscles or the upstream femoral artery alone was exposed to an endovascular ultrasound catheter (2.