Jean-Jacques Le Jeune

Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation

AIMS/METHODS Our aim was to study the antifibrotic and hemodynamic effects of simvastatin (SMV), pentoxifylline (PTX) and spironolactone (SPN), three drugs which may have antifibrotic and/or portal hypotensive properties, in a model of hepatic fibrosis and portal hypertension induced in rats by bile duct ligation. A blind study was performed in five groups of 53 Sprague-Dawley rats: sham, placebo (PL), SMV (2.5 mg x kg(-1) x J(-1)), PTX (50 mg x kg(-1) x J(-1)) and SPN (100 mg x kg(-1) x J(-1)). Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the following parameters were evaluated: area of hepatic fibrosis by image analysis after staining collagen with picrosirius and plasma concentrations of hyaluronate, splanchnic and systemic hemodynamics (radiolabeled microspheres). RESULTS Portal venous pressure (PL: 15.5+/-1.5, SMV: 15.8+/-2.5, PTX: 15.9+/-1.8, SPN: 13.5+/-2.1 mmHg, p<0.05) and porto-systemic shunts (PL: 30+/-31, SMV: 18+/-27, PTX: 25+/-24, SPN: 5+/-4%, p<0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. There was a significant correlation between portosystemic shunts and portal pressure (r(s)=0.47, p<0.01). The area of fibrosis was not significantly different among the four groups of bile duct ligated rats (PL: 8.7+/-3.9, SMV: 7.1+/-3.6, PTX: 7.8+/-2.7, SPN: 6.6+/-3.3%) but was higher than in sham rats (1.5+/-0.5%, p<0.001). Hyaluronate was significantly higher in bile duct ligated rats (from 374+/-162 to 420+/-131 microg/l, among the four groups) than in sham rats (52+/-16 microg/l, p<0.0001). CONCLUSIONS In this model, none of the drugs prevented hepatic fibrosis. On the other hand, spironolactone decreased portal pressure and prevented porto-systemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.

Regional assessment of wall curvature and wall stress in left ventricle with magnetic resonance imaging

Left ventricular functional abnormalities are associated with regional increases of wall stress and modifications of wall curvature. This study describes the integration of the short-axis and long-axis wall curvatures for determining peak systolic wall stress. Quantification was realized with cine magnetic resonance imaging (MRI) from the location of the endocardial and epicardial borders of the left ventricle on pairs of consecutive short-axis sections. Fifteen normal volunteers were subjected to cine MRI, and different methods of calculating peak systolic wall stress were compared. A short-axis analysis showed a 55 +/- 13% increase of the circumferential mean of the peak systolic wall stress between apical and basal sections. Regarding the curvature, no significant increase of wall stress was observed except on the septal wall (31 +/- 18%). Short-axis studies proved to be insufficient for determining the regional variations of left ventricular wall stress and for providing normal reference values for the location of abnormal regions in patients.

Three-dimensional coronary artery mr imaging using prospective real-time respiratory navigator and linear phase shift processing : Comparison with conventional coronary angiography

Respiratory gating with navigator echo is a recent technique to detect diaphragm position in 3D magnetic resonance (MR) coronary angiography. The purpose of our study was to image proximal coronary arteries and to detect significant stenoses in patients with coronary artery diseases and to compare with contrast enhanced angiography results. Twenty patients with coronary artery diseases who were referred for conventional angiography underwent magnetic resonance angiography (MRA). Three-dimensional gradient echo volumes were acquired using cardiac and respiratory gating and fat suppression. Using reformatted oblique planes and maximum intensity projection technique, visualization coronary segments and detection of significant coronary stenoses were made. Eighty-three coronary segments were analyzed. The sensitivity and specificity were 65% and 93%, respectively. The corresponding positive and negative predictive values were 69% and 91%. This study shows the ability to image correctly coronary arteries and to identify proximal stenoses, but image quality need to be improved for an efficiency detection of coronary artery stenoses in clinical practice.

Prevention of portal hypertension by propanolol and spironolactone in rats with bile duct ligation

BACKGROUND/AIMS It has been suggested that the early administration of propranolol (PR) and a low sodium diet may prevent the development of portosystemic shunts in animals with presinusoidal portal hypertension. Our aim was to study the hemodynamic effects of the early and chronic administration of PR and spironolactone (SPN), alone or in combination, in a model of hepatic fibrosis and sinusoidal portal hypertension induced in rats by bile duct ligation. METHODS A blind study was performed in 40 Sprague-Dawley rats divided into four groups: placebo (PL), PR (75 mg/kg per day), SPN (100 mg/kg per day), and PR+SPN at the same doses. Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the splanchnic and systemic hemodynamics (radiolabeled microspheres) were evaluated. RESULTS a) Systemic hemodynamics: PR significantly reduced cardiac index and increased vascular resistance, SPN had no significant effect and PR+SPN significantly decreased mean arterial pressure. b) Splanchnic hemodynamics: portal venous pressure (PL: 15.5 +/- 1.5, PR: 14.8 +/- 1.0, SPN: 13.5 +/- 2.1, PR+SPN: 15.0 +/- 1.3 mmHg, p < 0.05) and portosystemic shunts (PL: 30 +/- 31, PR: 13 +/- 14, SPN: 5 +/- 4, PR+SPN: 29 +/- 33%, p < 0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. In multivariate analysis, the only determinant of portosystemic shunts was portal pressure but with a low R2 (0.2). CONCLUSIONS In this model, the early administration of PR, alone or in combination with SPN, had no beneficial hemodynamic effects. On the other hand, SPN alone decreased portal pressure and prevented portosystemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.

Renal Changes on Hyperglycemia and Angiotensin-Converting Enzyme in Type 1 Diabetes

Hyperglycemia causes capillary vasodilation and high glomerular capillary hydraulic pressure, which lead to glomerulosclerosis and hypertension in type 1 diabetic subjects. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene can modulate risk of nephropathy due to hyperglycemia, and the II genotype (producing low plasma ACE concentrations and probably reduced renal angiotensin II generation and kinin inactivation) may protect against diabetic nephropathy. We tested the possible interaction between ACE I/D polymorphism and uncontrolled type 1 diabetes by measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) during normoglycemia ( approximately 5 mmol/L) and hyperglycemia ( approximately 15 mmol/L) in 9 normoalbuminuric, normotensive type 1 diabetic subjects with the II genotype and 18 matched controls with the ID or DD genotype. Baseline GFR (145+/-22 mL/min per 1.73 m2) and ERPF (636+/-69 mL/min per 1.73 m2) of II subjects declined by 8+/-10% and 10+/-9%, respectively, during hyperglycemia; whereas baseline GFR (138+/-16 mL/min per 1.73 m2) and ERPF (607+/-93 mL/min per 1.73 m2) increased by 4+/-7% and 6+/-11%, respectively, in ID and DD subjects (II versus ID or DD subjects: P=0.0007 and P=0.0005, for GFR and ERPF, respectively). The changes in renal hemodynamics of subjects carrying 1 or 2 D alleles were compatible, with a mainly preglomerular vasodilation induced by hyperglycemia, proportional to plasma ACE concentration (P=0.024); this was not observed in subjects with the II genotype. Thus, type 1 diabetic individuals with the II genotype are resistant to glomerular changes induced by hyperglycemia, providing a basis for their reduced risk of nephropathy.

Use of FDG-PET/CT for peritoneal carcinomatosis before hyperthermic intraperitoneal chemotherapy.

BackgroundPeritoneal carcinomatosis (PC) is associated with a very poor prognosis. Complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy has been shown to improve survival rates of PC. However, this treatment is beneficial for patients if the complete cytoreductive surgery is macroscopically completed before implementing hyperthermic intraperitoneal chemotherapy. Even so, a strict selection of patients is of fundamental importance because of the invasive nature of the intervention. The aim of this study was to assess the performance of FDG-PET/CT examinations for the diagnosis and evaluation of the extent of PC. MethodsA retrospective analysis was conducted on 28 consecutive patients with suspected PC, scheduled for a complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, and who underwent an FDG-PET/CT examination. We compared the results of PET examinations with histological and intraoperative findings. The extent of PC was assessed precisely using a simplified ‘peritoneal cancer index’, within the three modalities (PET, surgery and histology). ResultsOf 28 patients, 23 had histological PC. The sensitivity and specificity of the PET examination for the diagnosis of PC were, respectively, 82 and 100%. Even if the extent of PC was underestimated by PET, there was a good correlation when compared with histology and intraoperative results. ConclusionPET presented a good performance level in the diagnosis and evaluation of the extent of PC. PET/CT examinations could be useful to avoid unnecessary surgery.

Assessment of myocardial viability in rats: Evaluation of a new method using superparamagnetic iron oxide nanoparticles and Gd-DOTA at high magnetic field.

The aim of this study was to detect salvageable peri‐infarction myocardium by MRI in rats after infarction, using with a double contrast agent (CA) protocol at 7 Tesla. Intravascular superparamagnetic iron oxide (SPIO) nanoparticles and an extracellular paramagnetic CA (Gd‐DOTA) were used to characterize the peri‐infarction zone, which may recover function after reperfusion occurs. Infarcted areas measured from T1‐weighted (T1‐w) images post Gd‐DOTA administration were overestimated compared to histological TTC staining (52% ± 3% of LV surface area vs. 40% ± 3%, P = 0.03) or to T2‐w images post SPIO administration (41% ± 4%, P = 0.04), whereas areas measured from T2‐w images post SPIO administration were not significantly different from those measured histologically (P = 0.7). Viable and nonviable myocardium portions of ischemically injured myocardium were enhanced after diffusive Gd‐DOTA injection. The subsequent injection of vascular SPIO nanoparticles enables the discrimination of viable peri‐infarction regions by specifically altering the signal of the still‐vascularized myocardium. Magn Reson Med 52:932–936, 2004.

Three-dimensional MRI assessment of regional wall stress after acute myocardial infarction predicts postdischarge cardiac events

To determine the prognostic significance of systolic wall stress (SWS) after reperfused acute myocardial infarction (AMI) using MRI.

Noninvasive assessment of the infarct-related coronary artery blood flow velocity using phase-contrast magnetic resonance imaging after coronary angioplasty

This study assesses infarct-related coronary artery blood flow velocity using phase-contrast magnetic resonance imaging (MRI) in patients with reperfused acute myocardial infarction (AMI) and compares these results with flow measurements obtained nonsimultaneously by intracoronary Doppler ultrasound. MRI examination was performed in 17 patients with AMI within 1 to 4 days (mean 2.5 days) after direct or rescue coronary angioplasty using a 0.014-in Doppler guidewire. MRI was performed on a 1.5-T clinical imager. The fast gradient echo segmented k-space phase-contrast pulse sequence was employed during breath-hold. The MRI and Doppler parameters of average peak velocity and maximum peak velocity were measured. Mean phase contrast MRI average peak velocity was 13.3+/-10.7 cm/s, and mean phase-contrast MRI maximum peak velocity was 27+/-16.6 cm/s. Mean Doppler average peak velocity was 17.1+/-5.1 cm/s, and mean Doppler maximum peak velocity was 35.5+/-10.1 cm/s. At the same anatomic levels, phase-contrast MRI average peak velocity correlated significantly to Doppler average peak velocity (r = 0.52; p<0.006) and Doppler maximum peak velocity (r = 0.42; p<0.03). Phase-contrast MRI velocity measurements were correlated with the same heterogeneity of Thrombolysis In Myocardial Infarction 3 flow velocity observed during Doppler examination. Thus, by comparing phase-contrast MRI with invasive intracoronary Doppler flow measurements, the measured MRI values showed significant correlation with Doppler data. Phase-contrast MRI has the potential to noninvasively quantify coronary flow velocity and to evaluate quality of reperfusion in patients with AMI after reperfused therapy.

Synthesis of chelating molecules as agents for magnetic resonance imaging, 4 1 . Complexing properties of polycondensates prepared from diethylenetriaminepentaacetic acid bisanhydride

Abstract Chelating properties towards the metallic cation Cu2+ of polycondensates bearing aminoacetic acid groups along the polymer chain, synthesized from diethylenetriaminepentaacetic acid bisanhydride with diols and diamines, have been investigated. All the complexes are water soluble. Potentiometric titrations and visible and ultraviolet spectrophotometry show the formation of different complexes according to pH and dissociation constants point out the influence of the density of COOH groups along the polymer chain according to the diol or diamine comonomer. The behaviour of the synthesized polycondensates towards gadolinium has also been studied in order to evaluate their potential use as contrast agents for Magnetic Resonance Imaging by measure of the relaxivities of the obtained complexes.