Year-end Sale % OFF 
Abstract
RationaleAcute atherothrombotic occlusion in heart attack and stroke implies disruption of the vascular endothelial barrier that exposes a highly procoagulant intimal milieu. However, the evolution, severity, and pathophysiological consequences of vascular barrier damage in atherosclerotic plaque remain unknown, in part because quantifiable methods and experimental models are lacking for its in vivo assessment.ObjectiveTo develop quantitative nondestructive methodologies and models for detecting vascular barrier disruption in advanced plaques.Methods and ResultsSustained hypercholesterolemia in New Zealand White (NZW) rabbits for >7–14 months engendered endothelial barrier disruption that was evident from massive and rapid passive penetration and intimal trapping of perfluorocarbon-core nanoparticles (PFC-NP: ∼250 nm diameter) after in vivo circulation for as little as 1 hour. Only older plaques (>7 mo), but not younger plaques (<3 mo) demonstrated the marked enhancement of endothelial permeability to these particles. Electron microscopy revealed a complex of subintimal spongiform channels associated with endothelial apoptosis, superficial erosions, and surface-penetrating cholesterol crystals. Fluorine (19F) magnetic resonance imaging and spectroscopy (MRI/MRS) enabled absolute quantification (in nanoMolar) of the passive permeation of PFC-NP into the disrupted vascular lesions by sensing the unique spectral signatures from the fluorine core of plaque-bound PFC-NP.ConclusionsThe application of semipermeant nanoparticles reveals the presence of profound barrier disruption in later stage plaques and focuses attention on the disrupted endothelium as a potential contributor to plaque vulnerability. The response to sustained high cholesterol levels yields a progressive deterioration of the vascular barrier that can be quantified with fluorine MRI/MRS of passively permeable nanostructures. The possibility of plaque classification based on the metric of endothelial permeability to nanoparticles is suggested.
Highlights
The atherothrombotic syndromes of coronary heart disease, ischemic stroke and peripheral artery disease together account for 22% of all deaths worldwide (2004), with a prevalence of 26 million cases in the USA alone commanding a cost of greater than $4 billion/yr (2006) [1]
The application of semipermeant nanoparticles reveals the presence of profound barrier disruption in later stage plaques and focuses attention on the disrupted endothelium as a potential contributor to plaque vulnerability
The possibility of plaque classification based on the metric of endothelial permeability to nanoparticles is suggested
Summary
The atherothrombotic syndromes of coronary heart disease, ischemic stroke and peripheral artery disease together account for 22% of all deaths worldwide (2004), with a prevalence of 26 million cases in the USA alone commanding a cost of greater than $4 billion/yr (2006) [1]. The evolution and ultimate severity of endothelial permeability in response to long-term hypercholesterolemia has not been elucidated in experimental models or clinical subjects. The focal pathophysiological features that mark the evolution of late stage barrier disruption remain uncertain as a consequence of the lack of well accepted and robust experimental models that suitably represent the complexity of endothelial barrier disruption [14], and the lack of specific nondestructive diagnostic techniques that can quantify lesion severity. Acute experimental models of lipotoxic stress have been developed that elicit endothelial cell apoptosis as a precursor to vascular barrier disruption [15,16]. The aforementioned methods for studying endothelial function do not depict barrier disruption in vitro or in vivo because they generally reflect paracellular leakage in early stages of disease, as distinguished from later stage endothelial disruptions (erosion, micro-tears, etc.) that might portend more immediate clinical consequences
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
