Effect of rosiglitazone on progression of atherosclerosis: insights using 3D carotid cardiovascular magnetic resonance

<p>Abstract</p> <p>Background</p> <p>There is recent evidence suggesting that rosiglitazone increases death from cardiovascular causes. We investigated the direct effect of this drug on atheroma using 3D carotid cardiovascular magnetic resonance.</p> <p>Results</p> <p>A randomized, placebo-controlled, double-blind study was performed to evaluate the effect of rosiglitazone treatment on carotid atherosclerosis in subjects with type 2 diabetes and coexisting vascular disease or hypertension. The primary endpoint of the study was the change from baseline to 52 weeks of carotid arterial wall volume, reflecting plaque burden, as measured by carotid cardiovascular magnetic resonance. Rosiglitazone or placebo was allocated to 28 and 29 patients respectively. Patients were managed to have equivalent glycemic control over the study period, but in fact the rosiglitazone group lowered their HbA1c by 0.88% relative to placebo (P < 0.001). Most patients received a statin or fibrate as lipid control medication (rosiglitazone 78%, controls 83%). Data are presented as mean ± SD. At baseline, the carotid arterial wall volume in the placebo group was 1146 ± 550 mm³and in the rosiglitazone group was 1354 ± 532 mm³. After 52 weeks, the respective volumes were 1134 ± 523 mm³and 1348 ± 531 mm³. These changes (-12.1 mm³and -5.7 mm³in the placebo and rosiglitazone groups, respectively) were not statistically significant between groups (P = 0.57).</p> <p>Conclusion</p> <p>Treatment with rosiglitazone over 1 year had no effect on progression of carotid atheroma in patients with type 2 diabetes mellitus compared to placebo.</p

The effect of the elongation of the proximal aorta on the estimation of the aortic wall distensibility

The compliance of the proximal aortic wall is a major determinant of cardiac afterload. Aortic compliance is often estimated based on cross-sectional area changes over the pulse pressure, under the assumption of a negligible longitudinal stretch during the pulse. However, the proximal aorta is subjected to significant axial stretch during cardiac contraction. In the present study, we sought to evaluate the importance of axial stretch on compliance estimation by undertaking both an in silico and an in vivo approach. In the computational analysis, we developed a 3-D finite element model of the proximal aorta and investigated the discrepancy between the actual wall compliance to the value estimated after neglecting the longitudinal stretch of the aorta. A parameter sensitivity analysis was further conducted to show how increased material stiffness and increased aortic root motion might amplify the estimation errors (discrepancies between actual and estimated distensibility ranging from - 20 to - 62%). Axial and circumferential aortic deformation during ventricular contraction was also evaluated in vivo based on MR images of the aorta of 3 healthy young volunteers. The in vivo results were in good qualitative agreement with the computational analysis (underestimation errors ranging from - 26 to - 44%, with increased errors reflecting higher aortic root displacement). Both the in silico and in vivo findings suggest that neglecting the longitudinal strain during contraction might lead to severe underestimation of local aortic compliance, particularly in the case of women who tend to have higher aortic root motion or in subjects with stiff aortas

Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation

Background & Aims Liver transplantation from marginal donors is associated with ischemia/reperfusion (I/R) lesions, which may increase the risk of post-transplant hepatocellular carcinoma (HCC) recurrence. Graft reperfusion prior to retrieval (as for extracorporeal membrane oxygenation – ECMO) can prevent I/R lesions. The impact of I/R on the risk of cancer recurrence was assessed on a syngeneic Fischer-rat liver transplantation model. Methods HCC cells were injected into the vena porta of all recipients at the end of an orthotopic liver transplantation (OLT). Control donors were standard heart-beating, ischemic ones (ISC), underwent 10min or 30min inflow liver clamping prior to retrieval, and ischemic/reperfused (ISC/R) donors underwent 2h liver reperfusion after the clamping. Results I/R lesions were confirmed in the ISC group, with the presence of endothelial and hepatocyte injury, and increased liver function tests. These lesions were in part reversed by the 2h reperfusion in the ISC/R group. HCC growth was higher in the 10min and 30min ISC recipients ( p =0.018 and 0.004 vs. control, as assessed by MRI difference between weeks one and two), and was prevented in the ISC/Rs ( p =0.04 and 0.01 vs. ISC). These observations were associated with a stronger pro-inflammatory cytokine profile in the ISC recipients only, and the expression of hypoxia and HCC growth-enhancer genes, including Hmox1 , Hif1a and Serpine1 . Conclusions This experiment suggests that ischemia/reperfusion lesions lead to an increased risk of post-transplant HCC recurrence and growth. This observation can be reversed by graft reperfusion prior to retrieval

MRI micelles self-assembled from synthetic gadolinium-based nano building blocks

A synthetic nano building block endowed with amphiphilic properties and chelated gadoliniumis presented. Spontaneous self-assembly into small 12 nm corona-core stealth Gd-micelles with inherently high gadolinium loading occurs in water. Gd-Micelles are a new blood pool contrast agent with high relaxivity for magnetic resonance imaging

X-Ray diffraction and phosphorous-31 NMR studies of the dynamically disordered 3:2 phenol-triphenylphosphine oxide complex

The 3:2 phenol–triphenylphosphine oxide (phenol–TPPO) adduct was studied by means of X-ray diffraction together with high-resolution solid-state 31P NMR spectroscopy. The X-ray results showed that the crystalline structure, which belongs to the triclinic P[1 with combining macron] space group, involves disorder. There are two molecules of TPPO and three phenol molecules per unit cell. One of the latter is disordered across an apparent inversion centre. Analysis of NMR data in conjunction with the crystal structure allowed the origin of such disorder to be established, showing that it is dynamic in nature. Variable-temperature NMR experiments were performed and a coalescence temperature was found at 247 K. Spectra recorded below this temperature showed two phosphorus signals. The kinetics for the phenol residue exchanging between two different TPPO moieties (two-site exchange with equal populations) were determined. Thermodynamic parameters for the motion were calculated from Eyring plots. For temperatures ranging from 262.9 to 221.5 K, the bandshape analysis technique was used to derive the required data. For lower temperatures, the selective polarisation inversion experiment (SPI) was performed, whilst high temperature values were derived from variable-temperature T1ρ studies. The activation enthalpy (ΔH‡), calculated using the results obtained by bandshape analysis, T1ρ and SPI, was determined as 38 kJ mol−1, while the activation entropy (ΔS‡) was found to be −23 J mol−1 K−1 (assuming the transmission coefficient is ½). Phosphorus-31 shielding tensor anisotropies have been derived for this system by spinning sideband analysis at both fast and slow-exchange limits and it has been shown that the tensor is axially symmetric. Single-crystal experiments show that the symmetry axis of the tensor is along the P[double bond, length half m-dash]O bond (within experimental error)

Improved dynamic response assessment for intra-articular injected iron oxide nanoparticles

The emerging importance of nanoparticle technology, including iron oxide nanoparticles for monitoring development, progression, and treatment of inflammatory diseases such as arthritis, drives development of imaging techniques. Studies require an imaging protocol that is sensitive and quantifiable for the detection of iron oxide over a wide range of concentrations. Conventional signal loss measurements of iron oxide nanoparticle containing tissues saturate at medium concentrations and show a nonlinear/nonproportional intensity to concentration profile due to the competing effects of T₁ and T₂ relaxation. A concentration calibration phantom and an in vivo study of intra-articular injection in a rat knee of known concentrations of iron oxide were assessed using the difference-ultrashort echo time sequence giving a positive, quantifiable, unambiguous iron signal and monotonic, increasing concentration response over a wide concentration range in the phantom with limited susceptibility artifacts and high contrast in vivo to all other tissues. This improved dynamic response to concentration opens possibilities for quantification due to its linear nature at physiologically relevant concentrations