Molecular imaging of vascular phenotype

Our laboratory has pioneered non-invasive ultrasound molecular imaging of vascular phenotype. This technology relies on ultrasound contrast agents targeted to endothelial adhesion molecules, leukocyte markers, Von Willebrand factor (VWF), and platelets. We have applied these technologies in pre-clinical models in order to better understand the pathophysiology of disease initiation and progression for conditions that include atherosclerosis, microvascular ischemia-reperfusion injury, thrombotic angiopathies, and sickle cell disease. We have recently focused on imaging thromboinflammation involving abnormalities in the regulation of Von Willebrand Factor and subsequent platelet adhesion and inflammation. We have leveraged the ability to examine events at the blood pool-endothelial interface to evaluate novel therapies.

Microvascular function and dysfunction

We have pioneered the use of myocardial contrast echocardiography (MCE) and limb contrast-enhanced ultrasound (CEUS) for the assessment of microvascular function and dysfunction in the coronary circulation and in the peripheral (limb) microcirculation. Using quantitative perfusion imaging, we have been able to better understand mechanisms for microvascular dysfunction in the heart and skeletal muscle, and to test therapies for microvascular functional abnormalities in conditions such as peripheral artery disease, metabolic disease, hypertrophic cardiomyopathy, sickle cell disease, suspected primary microvascular dysfunction, and post-ischemic no-reflow. These studies have involved pre-clinical translational models (mice, non-human primates) and clinical studies. We are also engaged in a NASA-funded study to better understand potential microcirculation abnormalities associated with deep space missions by applying vasodilator stress MCE in astronauts.

Reversible mechanisms for aortic stenosis

Our laboratory’s molecular imaging research program investigating vascular thromboinflammation led to an unexpected finding indicating that aortic valve VWF and platelet adhesion contribute to rapidly-progressing aortic stenosis (AS) through platelet-derived factors such as TGFβ1. Our laboratory is using advanced non-invasive imaging, unique animal models, and clinical studies in humans to study how VWF-mediated platelet adhesion leads to myofibroblastic and osteogenic transformation of valve interstitial cells, and matrix remodeling; all of which contribute to the development of severe AS. Our intent is to reveal molecular mechanisms for AS that may respond to therapies that have not yet been tested in humans.

Therapeutic applications of ultrasound cavitation

The energy produced by acoustic cavitation has been leveraged for therapy. Our laboratory has contributed vital understanding of how microbubble contrast agents and other acoustically active agents can be used to focus and amplify the beneficial biologic effects of acoustic cavitation. We have pioneered protocols for loading microbubble carriers with genetic material and for tissue transfection or transduction, including AAV, by inertial cavitation of these agents. We have also pioneered the use of microbubble cavitation for augmenting tissue perfusion and reversing tissue ischemia. In the course of performing these studies, we have defined the molecular signaling pathways by which cavitation augments tissue perfusion through shear-mediated purinergic signaling which stimulates downstream calcium-dependent processes such as phosphorylation of eNOS and production of vasodilatory prostanoids. We are now engaged in FDA-approved clinical trials to examine the potential beneficial effects of cavitation energy.

Molecular Imaging for Clinical Diagnostics

The pipeline of novel molecular imaging technologies our laboratory has developed for studying disease pathobiology and treatment in pre-clinical models also has the potential to improve patient care by through new diagnostic algorithms. We believe that the principles of precision medicine in cardiovascular disease will be enhanced by phenotypic imaging with non-invasive methods. Probes we have developed against VCAM-1, selectins, platelet GPIbα, and VWF could be used to detect atherosclerosis at a very early stage, and to select individuals more likely to benefit from more advanced therapies. Probes targeted to VWF and platelets could also be used for early diagnosis of thrombotic angiopathies. Our pre-clinical efforts to develop a method for detecting recent but resolved ischemia (ischemic memory imaging) has been translated to humans using MCE molecular imaging and microbubbles containing phosphatidylserine.