Biomedical subjects

Yann Gouëffic

Publications and source records attributed to Yann Gouëffic.

9 recordsLinked to original sources

PubMed2006

Sirolimus blocks the accumulation of hyaluronan (HA) by arterial smooth muscle cells and reduces monocyte adhesion to the ECM.

Sirolimus (SRL), an inhibitor of human arterial smooth muscle cell (ASMC) proliferation and migration, prevents in-stent restenosis (ISR). Little is known about the effect of SRL on the extracellular matrix (ECM) component, hyaluronan, a key macromolecule in neointimal hyperplasia and inflammation. In this study, we investigated SRL regulation of the synthesis of hyaluronan by cultured human ASMC and the effect of SRL on hyaluronan mediated monocyte adhesion to the ECM. Hyaluronan production on a per cell basis was significantly inhibited by SRL at 4 days and remained so through 10 days. This reduction was correlated with reduced levels of hyaluronan synthase mRNAs while hyaluronan degradation rates were unchanged. Poly I:C, a viral mimetic, caused increased hyaluronan accumulation by ASMC cell layers and this increase was inhibited by SRL. The inhibition was paralleled by a reduction in hyaluronan-dependent monocyte adhesion to the ECM. This study demonstrates that SRL not only regulates the proliferation of ASMC but reduces the production of hyaluronan by these cells. This alteration in ECM composition results in reduced monocyte adhesion to the ECM in cultures of ASMC. Alterations in hyaluronan accumulation may contribute to the inhibition of ISR that is achieved by SRL.

Arteries↗

PubMed2006

Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation.

OBJECTIVE: Hyaluronan (HA) is an important constituent of the extracellular matrix and is known to regulate cellular events through binding to CD44 and the receptor for HA-mediated motility (RHAMM). Here we investigated the role of these receptors and the signaling pathways involved in HA-mediated effects in arterial smooth muscle cells (ASMC). METHODS: Effects of high-molecular weight HA (1 to 5 mg/ml) were analyzed in cultured ASMC from rat aorta. RESULTS: HA promoted actin stress fiber and lamellipodia formation and dose-dependently induced ASMC migration without effect on proliferation. Pull-down assay of Rho protein activity indicated that HA activated RhoA and Rac. HA-induced ASMC migration was not affected by the RhoA inhibitor Tat-C3 (10 microg/ml), the Rho kinase inhibitor Y-27632 (10 microM) and blocking anti-CD44 antibody ,but was reduced by the non-selective Rho protein inhibitor simvastatin (10 microM), the Rac inhibitor LT-toxin (1 mug/ml), small interfering RNA (siRNA) targeting Rac and the phosphatidyl inositol 3-kinase (PI3K) inhibitor LY294002 (25 microM), which also blocked HA-induced Rac activation. CD44 knockdown by siRNA inhibited HA-mediated RhoA activation without effect on ASMC migration. In contrast, siRNA targeting RHAMM inhibited both HA-induced migration and Rac activation. CONCLUSIONS: High-molecular weight HA independently activates RhoA and Rac through CD44 and RHAMM, respectively. HA-induced migration depends exclusively on RHAMM-mediated PI3K-dependent Rac activation.

Actins↗

PubMed2006

Percutaneous transplantation of genetically-modified autologous fibroblasts in the rabbit femoral artery: A novel approach for cardiovascular gene therapy.

OBJECTIVE: Arterial cell and gene therapies are promising strategies for the treatment of cardiovascular diseases; however, the optimal cell type and delivery technique for such treatment remain to be determined. The aim of the present study was to design a new approach for arterial cell and gene therapy in which genetically modified autologous skin fibroblasts are percutaneously delivered in stented rabbit femoral arteries in vivo. METHODS: Autologous skin fibroblasts underwent in vitro transfection with the cationic lipid FuGene and plasmids expressing the human form of the tissue inhibitor of metalloproteinase (hTIMP-1) or nls-LacZ reporter genes. RESULT: Transfection efficiency was about 50% and there were high levels of hTIMP-1 secretion up to 14 days after gene transfer. We demonstrated the feasibility of in vivo percutaneous transplantation of fluorescent fibroblasts in the rabbit femoral artery. Results were confirmed by scanning electron microscopy. In vivo local delivery of hTIMP-1-expressing fibroblasts in stented femoral arteries also resulted in high-levels of hTIMP-1 secretion ex vivo for 7 days. Fibroblast transplantation resulted in a modest increase in intimal hyperplasia at the target site, which was reversed with hTIMP-1-transfected fibroblasts. CONCLUSION: Percutaneous transplantation of genetically modified autologous fibroblasts could be used as a cellular platform for locoregional secretion of therapeutic proteins to treat either specific arterial diseases or the diseased organ (eg, the heart) supplied by the target artery. CLINICAL RELEVANCE: Cell and gene therapies are potential new treatments for cardiovascular diseases. We demonstrated that autologous fibroblasts could be easily harvested from a skin biopsy specimen, genetically modified in vitro with nonviral vectors, and percutaneously seeded in vivo in rabbit femoral arteries, leading to locoregional secretion of abundant amounts of recombinant proteins. This new approach has important advantages over alternative approaches that use endothelial cells, viral vectors, and intraoperative cell delivery. Clinical applications may include local treatment of atherosclerotic plaques or aneurysms and also treatment of the diseased organs supplied by the target artery (eg, ischemic or failing heart).

Animals↗

PubMed2005

Association of aneurysmal and occlusive lesions in Behçet's disease.

Arterial involvement in Behçet's disease is rare, occurring in various locations with multiple clinical expressions. When Behçet's disease is associated with large arteries, lesions are usually in the form of aneurysms or occlusions. The simultaneous occurrence of these two lesions is even more unusual. We present a case of Behçet's disease in which arterial involvement included an iliac artery thrombosis and an asymptomatic aneurysm of the infrarenal abdominal aorta. Behçet's disease must be considered in the diagnosis of any unexplained inflammatory arteriopathy. Surgery is indicated for the majority of aneurysms and severe symptoms. The postoperative follow-up is based on noninvasive radiologic examinations.

Adult↗

PubMed2005

Evidence for early nasogastric tube removal after infrarenal aortic surgery: a randomized trial.

OBJECTIVE: Nasogastric tube (NGT) decompression after abdominal surgery is still largely used to prevent nausea and vomiting. However, indications are based more on practice than on studies. Moreover, prolonged NGT decompression can lead to complications. In this prospective and randomized study, we evaluated the effects of early withdrawal of NGTs in patients undergoing surgery of the infrarenal aorta. METHODS: Between October 2001 and May 2002, consecutive patients underwent scheduled infrarenal aortic operations. Patients were prospectively randomised into two groups: group 1, NGT maintenance until the passage of flatus; and group 2, NGT removal at the time of tracheal extubation. Preoperative and perioperative data were collected. The main end point was the occurrence of nausea and vomiting. Secondary end points were tolerance of NGT withdrawal and postoperative complications. Criteria were compared between groups by using Mann-Whitney or Fisher exact tests. RESULTS: Forty-six patients underwent aortic operations. Six patients were subsequently excluded from the study. Of the 40 randomized subjects, 20 patients were included in each group. Preoperative and intraoperative data were similar in both groups. There was no statistical difference between groups regarding nausea and vomiting. In group 1, the occurrence of respiratory complications was more frequent compared with group 2 (5 vs 0 complications; P = .023). There was no significant difference in intensive care unit stay, but the hospital stay was shorter in group 2 (mean, 9 +/- 3 days vs 15 +/- 9 days; P = .016). There were no differences in other adverse events. CONCLUSIONS: This study does not support a significant effect of early removal of NGTs on nausea and vomiting in patients undergoing open repair of the infrarenal aorta. However, these findings suggest that NGT maintenance increases the risk of respiratory complications and the length of hospital stay.

Aged↗

PubMed2005

Midterm survival after endovascular versus open repair of infrarenal aortic aneurysms.

PURPOSE: To report the midterm survival after endovascular repair (ER) of infrarenal aortic aneurysms and to compare the outcomes to contemporaneous patients treated with open repair (OR). METHODS: Between January 1995 and December 2001, 498 patients were treated for abdominal aortic aneurysm: 289 (52%) underwent OR and 209 (48%) underwent ER at a single center. Preoperative risk factors were graded according to the SVS/AAVS risk stratification. A computerized database was used to record demographic, clinical, and follow-up data. RESULTS: Significant benefits (p<0.0001) were observed in the ER group in terms of mean procedural time (163+/-66 versus 132+/-61 minutes), mean blood loss (1268+/-923 versus 122.5+/-284 mL), and mean hospital length of stay (16.24+/-13.3 versus 9.3+/-11.6 days). The perioperative mortality for OR and ER patients were, respectively, 5.1% and 1.5% (p=0.04). The mean follow-up was 40 months in the OR group (range 0-85) and 19 months in the ER group (range 2-80). Contact was lost with 31 (6%) patients during the study. No overall survival advantage was observed for OR over ER, and comparison of OR and ER according the risk classifications did not yield any significant differences. No patients died of aneurysm rupture, but 7 ER patients had to be converted to open surgery. The cumulative freedoms from reinterventions at 4 years for the OR and ER groups, respectively, were 87% and 63% (p=0.001). Patients treated by OR had better clinical success (p=0.001). Patients in the ER group without iliac artery aneurysm showed a significant improvement (p=0.035) over patients with aneurysmal iliac arteries. CONCLUSIONS: Over the 7 years of this study, ER realized its goal: prevention of aneurysm rupture. Despite a greater number of reinterventions for ER patients, no overall survival difference was observed.

Adult↗

PubMed2004

[Prevention of in-stent restenosis: towards an in situ treatment?].

The use of intracoronary stents represent a major breakthrough in the armamentarium of interventional cardiology. Stents reduce significantly the incidence of recurrent stenosis (in-stent restenosis) via an improved post-procedure luminal diameter and an abrogation of the constrictive remodeling of the arterial wall. However, stent-related arterial injury results in intense proliferative and inflammatory responses and severe intimal hyperplasia, which, in 20% to 40% of the patients, may end up with clinically significant in-stent restenosis. Efficient prevention of in-stent restenosis has yet to be found. Systemic treatments have failed because they don't take into account the specific physiopathology and, most importantly, the focal nature of in-stent intimal hyperplasia. Hence, local prevention appears to be a straightforward approach to the unsolved issue of in-stent restenosis. In situ beta- or gamma-irradiation (brachytherapy) has received much attention as a curative treatment of in-stent restenosis but is not indicated for prevention. In contrast, drug-releasing stents have been tested in experimental models and have already provided very promising results in randomized clinical trials. Most of clinical studies have been performed with the antiproliferative agents sirolimus and paclitaxel, but other agents are under scrutiny. In addition, important research is carried out, in which the efficacy of antiproliferative genes is investigated. Clearly, drug-releasing stents are on the verge of profoundly modifying our practice of interventional cardiology. However, several questions remain unanswered as regard to the long term efficacy/toxicity and the cost-effectiveness of this new approach.

Animals↗

PubMed2002

Superior mesenteric artery dissection: case report.

Spontaneous dissections of the superior mesenteric artery are exceptional events because only 26 reports have been published. We present a new case, revealed with an acute abdominal syndrome. Computed tomographic angiography and arteriography allowed a rapid diagnosis and urgent surgical intervention. Progress in imagery makes diagnosis and follow-up examination easier. Surgery is indicated for acute symptomatic forms with suspicion of mesenteric ischemia. In the other cases, a simple follow-up examination may be appropriate.

Dissection↗

PubMed2002

Surgical treatment of nonaneurysmal aortic arch lesions in patients with systemic embolization.

PURPOSE: Atherosclerotic lesions of the aortic arch are potential sources of arterial embolism. Here we investigate whether surgery, with the necessary circulatory supports, can be proposed as a good option for treatment of this problem. Study of these lesions on a national scale in France has made possible the assessment for future indications of techniques and results of the surgical management of aortic arch lesions, which retrospectively proved to be embolic. METHODS: Thirty-eight patients, (19 men and 19 women) underwent surgery between 1976 and 1996 in 17 French cardiovascular surgical centers. The average age at the time of surgery was 49 +/- 12 years (range, 31 to 82 years). Atherosclerotic lesions were detected with transesophagial echocardiography (n = 19), angiography of the aortic arch (n = 16), computed tomography (n = 9), and magnetic resonance imaging (n = 10). Surgery consisted of thrombectomy and endarterectomy (n = 22), aortic resection and graft replacement (n = 10), and patch aortoplasty (n = 5; one thrombus disappeared spontaneously before surgery was performed). RESULTS: The average postoperative period was 30 months (range, 3 to 82 months). Contact was lost with four patients after a follow-up period of 12 months. On pathologic specimens obtained at surgery, an atherosclerotic plaque was found in 73% of the cases (n = 28). In 15% of the cases, the aorta appeared normal (n = 6) and four other types of lesion were identified: angiosarcoma (n = 1), ectasia at the insertion of the remains of the ductus arteriosus (n = 1), rupture of tunica intima (n = 1), and a fibroblastic plaque (n = 1). A thrombus was identified in 26 cases, attached to the arterial wall in 18 cases. When transesophagial echocardiographic results showed mobile lesions (n = 22), histopathologic examination of specimens allowed the detection of a thrombus in 18 cases and an atherosclerotic plaque with a mobile projection in four cases. The postoperative mortality rate was 2.6%. The morbidity rate (28.9%; n = 11) was related to neurologic complications (n = 6), vascular complications (n = 4), and infection (n = 1). Four cases (12%) were reoperated. CONCLUSION: Nonaneurysmal aortic arch lesions are a frequent and still underestimated source of stroke and peripheral embolization. Surgery with circulatory support can be recommended in good operative candidates with recurrent critical events despite medical management and with high embolic potential (young patients with no calcified plaques).

Adult↗