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The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques.

ABSTRACT: We have previously reported enhancing the imaging of atherosclerotic plaques in mice using reconstituted high density lipoproteins (HDL) as nanocarriers for the MRI contrast agent gadolinium (Gd). This study focuses on the underlying mechanisms of Gd delivery to atherosclerotic plaques. HDL, LDL, and VLDL particles containing Gd chelated to phosphatidyl ethanolamine (DTPA-DMPE) and a lipidic fluorophore were used to demonstrate the transfer of Gd-phospholipids among plasma lipoproteins in vitro and in vivo. To determine the basis of this transfer, the roles of phospholipid transfer protein (PLTP) and lipoprotein lipase (LpL) in mediating the migration of Gd-DTPA-DMPE among lipoproteins were investigated. The results indicated that neither was an important factor, suggesting that spontaneous transfer of Gd-DTPA-DMPE was the most probable mechanism. Finally, two independent mouse models were used to quantify the relative contributions of HDL and LDL reconstituted with Gd-DTPA-DMPE to plaque imaging enhancement by MR. Both sets of results suggested that Gd-DTPA-DMPE originally associated with LDL was about twice as effective as that injected in the form of Gd-HDL, and that some of Gd-HDL's effectiveness in vivo is indirect through transfer of the imaging agent to LDL. In conclusion, the fate of Gd-DTPA-DMPE associated with a particular type of lipoprotein is complex, and includes its transfer to other lipoprotein species that are then cleared from the plasma into tissues.

SUBMITTER: Barazza A

PROVIDER: S-EPMC3928357 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques.

Barazza Alessandra A Blachford Courtney C Even-Or Orli O Joaquin Victor A VA Briley-Saebo Karen C KC Chen Wei W Jiang Xian-Cheng XC Mulder Willem J M WJ Cormode David P DP Fayad Zahi A ZA Fisher Edward A EA

Bioconjugate chemistry 20130510 6

We have previously reported enhancing the imaging of atherosclerotic plaques in mice using reconstituted high density lipoproteins (HDL) as nanocarriers for the MRI contrast agent gadolinium (Gd). This study focuses on the underlying mechanisms of Gd delivery to atherosclerotic plaques. HDL, LDL, and VLDL particles containing Gd chelated to phosphatidyl ethanolamine (DTPA-DMPE) and a lipidic fluorophore were used to demonstrate the transfer of Gd-phospholipids among plasma lipoproteins in vitro ...[more]

PMID: 23617731

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Project description:Background and purposeContrast enhancement of intracranial atherosclerotic plaques has recently been investigated using high field and high resolution MR imaging as a risk factor in the development of ischemic stroke. We studied the reliability of conventional MR imaging at 1.5T in evaluating intraplaque enhancement and its relationship with acute cerebrovascular ischemic presentations in patients with severe intracranial atherosclerotic disease.Materials and methodsWe retrospectively identified and analyzed 19 patients with 22 high-grade intracranial atherosclerotic disease plaques (>70% stenosis) in vessels cross-sectionally visualized by neuroanatomic MR imaging. Atherosclerotic plaques were classified as asymptomatic or symptomatic. Two blinded neuroradiologists independently ranked each lesion for the presence of intraplaque enhancement by use of a 5-point scale (1-5). Furthermore, plaque enhancement was quantified as the relative change in T1WI spin-echo signal intensity (postcontrast/precontrast) in the vessel wall at the site of each intracranial atherosclerotic disease lesion.ResultsIntraplaque enhancement was observed in 7 of 10 (70%) symptomatic plaques, in contrast to 1 of 12 (8%) asymptomatic plaques. Interobserver reliability correlated well for intraplaque enhancement (κ = 0.82). The degree of relative plaque enhancement in symptomatic versus asymptomatic lesions (63% versus 23%) was statistically significant (P = .001, t test).ConclusionsIn this pilot study, we determined that intraplaque enhancement could be reliably evaluated with the use of cross-sectional imaging and analysis of vessels/plaques by use of conventional neuroanatomic MR imaging protocols. In addition, we observed a strong association between intraplaque enhancement in severe intracranial atherosclerotic disease lesions and ischemic events with the use of conventional MR imaging. Our preliminary study suggests that T1 gadolinium-enhancing plaques may be an indicator of progressing or symptomatic intracranial atherosclerotic disease.

Project description:It is uncertain whether pharmacological reductions in very-low-density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low-density lipoprotein cholesterol (LDL-C) has been adequately lowered. We examined whether individuals with greater on-statin reductions in VLDL-related measures-beyond reductions in LDL-C-were at further reduced risk of ASCVD.In 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400-MHz proton nuclear magnetic resonance spectroscopy-measured VLDL particle subclasses (small, medium, and large VLDL lipoprotein particle concentration), and total VLDL cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin-allocated participants who achieved minimal (<median) or greater (?median) marker reductions using adjusted Cox models. On-statin changes in VLDL-related markers were only modestly correlated (Spearman r?0.29) with change in LDL-C. On-statin median LDL-C was 54 mg/dL and triglyceride was 101 mg/dL. Dose-response reductions in ASCVD risk were observed for greater reductions in LDL-C, VLDL cholesterol mass, and small VLDL lipoprotein particle concentration; the latter 2 remained significant after incremental adjustment for change in LDL-C (P?0.006). Conversely, there was no further risk reduction with greater reductions in triglycerides or large/medium VLDL lipoprotein particle concentration.Pharmacological reduction in small, cholesterol-enriched, triglyceride-depleted VLDL was associated with reduction in ASCVD risk. Chemically measured triglycerides may not sufficiently capture risk related to VLDL pathways. These findings also support broader profiling of lipid and lipoprotein changes in response to statins as prognostic markers of individual benefit, supporting more precision-medicine, individualized approaches to cardiovascular risk reduction.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Dataset Information

The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques.

Publications

The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques.

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