Camille Brasselet

Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study

BACKGROUND Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model. METHODS We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation. FINDINGS Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9.9% (range -20 to 0.3) relative to baseline (p=0.011) whereas in the treated group it improved by 6.6% (-5.7 to 50.8; comparison between groups p=0.002). INTERPRETATION These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.

Randomised comparison of femoral versus radial approach for percutaneous coronary intervention using abciximab in acute myocardial infarction: results of the FARMI Trial

Objective: To compare bleeding complications and results of percutaneous coronary intervention (PCI) between patients treated by radial and femoral approaches for acute myocardial infarction (AMI,) and using abciximab and 5 French guiding-catheters. Patients: 114 consecutive patients with AMI were prospectively randomised. Exclusion criteria were a history of coronary artery bypass graft, cardiogenic shock, atrioventricular block, and contraindication to abciximab or a negative Allen test. Local haemostasis was achieved by manual compression. Results: Baseline characteristics were similar between the two groups. Peripheral arterial complication rates and delays to patient ambulation were significantly lower in the radial group than in the femoral group, whereas in-hospital stay was similar between the two groups. A cross over was more often necessary in the radial group than in the femoral group. Coronary angiography duration and fluoroscopy time were significantly longer in the radial group than in the femoral group, whereas PCI duration was similar in both groups. Conclusions: The FARMI trial showed that the radial route lowered peripheral arterial complication rates and allowed earlier ambulation, despite no significant benefit on the duration of hospitalisation.

Effect of adenovirus-mediated overexpression of decorin on metalloproteinases, tissue inhibitors of metalloproteinases and cytokines secretion by human gingival fibroblasts

Decorin is a small leucine-rich proteoglycan that plays a role in control of cell proliferation, cell migration, collagen fibrillogenesis and modulation of the activity of TGF-beta. In the present study, we investigated the effects of decorin on the production of metalloproteinases (MMP-1, -2, -3, -9 and -13), tissue inhibitors of metalloproteinases (TIMP-1, -2) and cytokines (TGF-beta, IL-1beta, IL-4 and TNF-alpha). Decorin was overexpressed in cultured human gingival fibroblasts using adenovirus-mediated gene transfer. Decorin infection resulted in decreased protein levels of MMP-1 and MMP-3 whereas MMP-2 and TIMP-2 secretion was increased. MMP-9, MMP-13 and TIMP-1 were not affected by decorin infection. Cytokine measurements by ELISA showed that decorin overexpression reduced TGF-beta and IL-1beta. In contrast, IL-4 and TNF-alpha levels were markedly increased in decorin-infected cells. These results suggest that decorin could modulate the expression of certain metalloproteinases and their inhibitors, as well as the production of cytokines. Altogether, our data suggest that decorin might play a pivotal role in tissue remodeling by acting on the balance between extracellular matrix synthesis and degradation.

Adenovirus-Mediated Gene Transfer of Superoxide Dismutase and Catalase Decreases Restenosis after Balloon Angioplasty

Background: Reactive oxygen species (ROS) production increases after injury and potentially contributes to restenosis after angioplasty. We therefore evaluated the effect of adenovirus-mediated gene transfer (Ad) of superoxide dismutase (SOD) and catalase (CAT) on ROS production and restenosis after balloon angioplasty. Methods: O2– and H2O2 production was quantified in cultured cells after incubation with either LPS or CuSO4. Angioplasty and gene transfer were performed in rabbit atherosclerotic iliac arteries. One artery was injected with AdSOD and AdCAT, while the contralateral artery was injected with an adenovirus carrying no transgene, and served as control. Results: ROS production was significantly decreased after adenovirus-mediated gene transfer of SOD and CAT as compared with control. Treated arteries showed less restenosis (32 ± 27 vs. 63 ± 19%, p = 0.003) and less constrictive remodeling (1.2 ± 0.3 vs. 0.9 ± 0.2, p = 0.02) than control arteries. Arteries injected with AdSOD and AdCAT showed better vasoreactivity to acetylcholine (11 ± 4 vs. –1 ± 6%, p < 0.05), lower collagen density (43 ± 16 vs. 53 ± 23%, p = 0.03), and lower inflammatory cell infiltration (22 ± 6 vs. 36 ± 11%, p = 0.04) than control arteries. Conclusions: Our data suggest that adenovirus-mediated gene transfer of SOD and CAT reduced oxidative stress, restenosis, collagen accumulation, and inflammation and improved endothelial function after angioplasty.

Adjusting a polymer formulation for an optimal bioresorbable stent: a 6-month follow-up study.

AIMS To assess the impact of the composition in L- and D- of lactic acid stereo copolymers without drug elution on the in situ behaviour of prototype stents in terms of biomechanics and biocompatibility. METHODS AND RESULTS PLA50, 75, and 92 stereo-copolymer stents (L/D lactic acid ratio from 1 to 11.5) were processed using the injection moulding facilities of Arterial Remodeling Technologies (Noisy le Roi, France). The resulting 3 mm outer diameter tubes having a diameter at the desired nominal size were laser-cut and crimped on regular angioplasty balloons and chemically sterilised prior to implantation in iliac rabbit arteries. Acute recoil was higher in PLA50 and PLA75 stent-treated arteries than in those with PLA92 stents (17.4 ± 11.4 vs. 13.5 ± 7.6 vs. 4.1 ± 3.8 %, respectively, p=0.001). At one month, in-stent area was higher in PLA92 than in PLA50 and PLA75 stented arteries (5.9 ± 0.6 vs. 1.6 ± 1.6 vs. 2.6 ± 3.2 mm², respectively, p<0.001). Re-endothelialisation was complete, and inflammation was mild around the struts, similar among the three stents. Late lumen loss and neointimal area were low and similar in PLA92 stent-treated arteries one and six months after angioplasty (0.2 ± 0.2 vs. 0.3 ± 0.2 mm, p=0.60; 0.5 ± 0.5 vs. 0.5 ± 0.8 mm², p=0.72, respectively). At six months, inflammation decreased compared to one-month follow-up (1.4 ± 0.5 vs. 0.6 ± 0.5, p=0.006). CONCLUSIONS A stereo-copolymer composition strongly influences biomechanical properties of PLA bioresorbable stents in agreement with what has been known for a long time from other applications, but not biocompatibility. PLA92 stents appeared as presenting acceptable acute deployment and 6-month favourable outcome in the rabbit model despite the absence of drugs.

Percutaneous coronary intervention-induced variations in systemic parameters of inflammation: relationship with the mode of stenting.

Abstract Background: During percutaneous coronary intervention, the technique of stent implantation (both direct and complementary stenting) is guided using both clinical and angiographic features. We assessed potential relationships between procedural parameters and angioplasty-induced variations in inflammatory parameters in patients treated by these two different techniques. Methods: A total of 85 consecutive patients due to undergo stent implantation were prospectively enrolled. Inflammation was assessed in terms of C-reactive protein, fibrinogen, erythrocyte sedimentation rate and leukocyte count in samples taken before and 24 h after angioplasty. Patients were classified based on whether they underwent complementary (n=47) or direct stenting (n=38). Results: Inflammation after complementary stenting was related to the duration of inflation (r=0.59; p<0.001), whereas inflammation after direct stenting was related to the inflation pressure (r=0.61; p=0.007), as assessed by C-reactive protein variation. None of the other parameters influenced the inflammatory response. Conclusions: The inflammatory response after stent implantation depends on the mode of stenting. We therefore hypothesize that the inflammatory response after stenting might be related to the histological composition of the atherosclerotic plaques involved. Clin Chem Lab Med 2007;45:526–30.

0113: Factors associated with infarct-related artery patency before primary percutaneous coronary intervention for ST-elevation myocardial infarction: results from the FAST-MI 2010 registry

Background Early infarct-related artery (IRA) patency is associated with better clinical outcomes in STEMI patients. Using the FAST-MI 2010 ST-elevation myocardial infarction (STEMI) cohort, we investigated factors related to IRA patency (TIMI 2/3 flow) at the start of procedure in patients admitted for primary percutaneous coronary intervention (PCI). Methods and results FAST-MI 2010 is a nationwide French registry including 4,169 Acute MI patients. Of 1452 STEMI patients with primary PCI, 466 (32%) had TIMI 2/3 flow of IRA before the procedure. Mean age (62±14 years in both groups), GRACE score (141±31 vs 142±34) and time from onset to angiography (472±499 vs 451±479min) did not differ according to IRA patency (TIMI2/3 vs TIMI 0/1). Using multivariate logistic regression analysis, IRA patency was more frequently found in patients having called earlier ( 90min, OR: 1,38; 95%IC 1.08-1.77). The results were confirmed by propensity score analyses. Conclusion Pre-procedural IRA patency is observed in one third of STEMI patients; it is more frequently found in patients having received APT prior to angiography, as well as in patients having called early. Higher IRA patency with increasing time delays from qualifying ECG to angiography suggests an additional role of spontaneous or medication-mediated fibrinolysis.