MRI-determined carotid artery flow velocities and wall shear stress in a mouse model of vulnerable and stable atherosclerotic plaque

Objectives\u3cbr/\u3eWe report here on the pre-clinical MRI characterization of an apoE−/− mouse model of stable and vulnerable carotid artery atherosclerotic plaques, which were induced by a tapered restriction (cast) around the artery. Specific focus was on the quantification of the wall shear stress, which is considered a key player in the development of the plaque phenotype.\u3cbr/\u3e\u3cbr/\u3eMaterials and methods\u3cbr/\u3eIn vivo MRI was performed at 9.4 T. The protocol consisted of time-of-flight angiography, high-resolution T1- and T2-weighted black-blood imaging and phase-contrast flow velocity imaging as function of time in the cardiac cycle. Wall shear stress was determined by fitting the flow profile to a quadratic polynomial.\u3cbr/\u3e\u3cbr/\u3eResults\u3cbr/\u3eTime-of-flight angiography confirmed preservation of blood flow through the carotid arteries in all cases. T1- and T2-weighted MRI resulted in high-resolution images in which the position of the cast, luminal narrowing introduced by cast and plaque, as well as the arterial wall could be well identified. Laminar flow with low wall shear stress (11.2± 5.2 Pa) was measured upstream to the cast at the position of the vulnerable plaque. Downstream to the cast at the position of the stable plaque, the apparent velocities were low, which is consistent with vortices and an oscillatory nature of the flow.\u3cbr/\u3e\u3cbr/\u3eConclusions\u3cbr/\u3eFlow velocities and wall shear stress were successfully measured in this mouse model of stable and unstable plaque. The presented tools can be used to provide valuable insights in the pathogenesis of atherosclerosis

Molecular MR imaging of collagen in mouse atherosclerosis by using paramagnetic CNA35 micelles

Magnetic resonance imaging (MRI) is increasingly used in biomedicine to visualize plaques in the walls of major arteries in relation to atherosclerosis, the prime cause of myocardial infarction and ischemic stroke. The present study aims to explore the utility of contrast-enhanced MRI for improving the specificity of the MRI evaluation of atherosclerotic plaques with the use of a Gd-based paramagnetic contrast agent that is targeted to collagen. Collagen is a major component of the extracellular matrix and as such plays an important role in the stability of atherosclerotic plaques. Micelles were made with lipid containing 45 mol-% Gd for MRI detection and a low mol fraction of fluorescent lipid for fluorescence microscopic analysis. Collagen-targeted, functional micelles were prepared by conjugation of the CNA35 protein, while nonfunctional control micelles were conjugated with a mutated version of the protein. The micelles were characterized with respect to their magnetic, biochemical, and biophysical properties. Atherosclerotic plaques were induced in the right carotid artery of apo-E knock-out mice by surgical placement of a tapered polymeric cast. In vivo MRI was performed at 6.3 Tesla before and up to 24 h after intravenous injection of paramagnetic micelles (50 µmol Gd kg -1). MRI revealed the strongest signal enhancements by CNA35 micelles. At early time points after injection of CNA35 micelles, contrast enhancement was higher in the collagen-richer lesions compared to that in the collagen-poorer lesions. Confocal laser scanning microscopy confirmed co-localization of CNA35 micelles and collagen in the plaques. We have demonstrated molecular MR imaging of collagen in experimental atherosclerosis by using a CNA35-functionalized micellar contrast agent